Pharmacology of the GABAA Receptor
Basic Neuropharmacology
Dmytro Berezhnoy,
Maria C. Gravielle,
David H. Farb,
Dmytro Berezhnoy
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorMaria C. Gravielle
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorDavid H. Farb
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorDmytro Berezhnoy,
Maria C. Gravielle,
David H. Farb,
Dmytro Berezhnoy
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorMaria C. Gravielle
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorDavid H. Farb
Boston University School of Medicine, Laboratory of Molecular Neurobiology, Boston, Massachusetts
Search for more papers by this authorAbstract
GABA mediates most inhibitory synaptic transmission in the adult vertebrate CNS by activating type-A GABA receptors that contain an integral ion channel and type-B GABA receptors that are G-protein coupled. GABAA receptors have been a rich target for the development of therapeutics for treatment of anxiety disorders, convulsive disorders, sleep disturbances, and for the induction of anesthesia. GABAA receptors are composed of five membrane-spanning subunits, selected from eight subunit subtypes (α, β, γ, δ, η, ρ, π, and θ) many of which contain multiple isoforms yielding at least 21 distinct subunit variants. These variations in subunit composition can have profound effects upon the functionality, pharmacology, and subcellular distribution of receptor subtypes. This chapter focuses on the relationship between receptor architecture and pharmacology of a large number of clinically relevant compounds such as benzodiazepines, barbiturates, anesthetics, neurosteroids and alcohols.
References
- 1 Bloom, F. E., and Iversen, L. L. (1971). Localizing 3H-GABA in nerve terminals of rat cerebral cortex by electron microscopic autoradiography. Nature 229, 629–630.
- 2 Sivilotti, L., and Nistri, A. (1991). GABA receptor mechanism in the central nervous system. Prog. Neurobiol. 36, 35–92.
- 3
Freund, T. F., and
Buzsaki, G.
(1996).
Interneurons of the hippocampus.
Hippocampus
6,
347–470.
10.1002/(SICI)1098-1063(1996)6:4<347::AID-HIPO1>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 4 Kuffler, S. W., and Edwards, C. (1958). Mechanism of gamma-aminobutyric acid (GABA) action and its relation to synaptic inhibition. J. Neurophysiol. 21, 589–610.
- 5 Kravitz, E. A. (1963). Gamma-aminobutyric acid and other blocking compounds in crustacea. III. Their relative concentrations in separated motor and inhibitory axons. J. Neurophysiol. 49, 831–850.
- 6 Otsuka, M., Iversen, L. L., Hall, Z. W., and Kravitz, E. A. (1966). Release of γ-aminobutyric acid from inhibitory nerves of lobster. Proc. Nat. Acad. Sci. USA 56, 1110–1115.
- 7Hayashi, T., and Nagai, K. (1956). Action of γ-amino acids on the motor cortex of higher animals, especially γ-amino-β-oxy-butyric acid as the real inhibitory principle in brain. Paper presented at the Twentieth International Physiology Congress, Brussels, p. 410.
- 8 Bazemore, A. W., Elliot, K. A. C., and Florey, E. (1957). Isolation of factor I. J. Neurochem. 1, 334–339.
- 9 Krnjevic, K., and Schwartz, S. (1967). The action of γ-aminobutyric acid on cortical neurons. Exp. Brain Res. 3, 320–336.
- 10 Dreifuss, J. J., Kelly, J. S., and Krnjevic, K. (1969). Cortical inhibition and γ-aminobutyric acid. Exp. Brain Res. 9, 137–154.
- 11 Choi, D. W., Farb, D. H., and Fischbach, G. D. (1977). Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature 269, 342–344.
- 12 Choi, D. W., Farb, D. H., and Fischbach, G. D. (1981). GABA-mediated synaptic potentials in chick spinal cord and sensory neurons. J. Neurophysiol. 45, 632–643.
- 13 Choi, D. W., Farb, D. H., and Fischbach, G. D. (1981). Chlordiazepoxide selectively potentiates GABA conductance of spinal cord and sensory neurons in cell culture. J. Neurophysiol. 45, 621–631.
- 14 Farb, D. H., Berg, D. K., and Fischbach, G. D. (1979). Uptake and release of [3H]GABA by embryonic spinal cord neurons in dissociated cell culture. J. Cell Biol. 80, 651–661.
- 15 Rabow, L. E., Russek, S. J., and Farb, D. H. (1995). From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse 21, 189–274.
- 16 Russek, S. J., and Farb, D. H. (1994). Mapping of the β2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABAA receptor isoform. Genomics 23, 528–533.
- 17 McLean, P. J., Farb, D. H., and Russek, S. J. (1995). Mapping of the alpha 4 subunit gene (GABRA4) to human chromosome 4 defines an α2-α4-β1-γ1 gene cluster: Further evidence that modern GABAA receptor gene clusters are derived from an ancestral cluster. Genomics 26, 580–586.
- 18 Russek, S. J. (1999). Evolution of GABAA receptor diversity in the human genome. Gene 227, 213–222.
- 19 Ribak, C. E., Vaughn, J. E., Saito, K., Barber, R., and Roberts, E. (1977). Glutamate decarboxylase localization in neurons of the olfactory bulb. Brain Res. 126, 1–18.
- 20Martin, D. L., and Tobin, A. J. (2000). GABA in the Nervous System. Lippincott, Williams & Wilkins, Philadelphia, pp. 25–41.
- 21Iversen, L. L. (1975). Handbook of Psychopharmacology. Plenum, New York, pp. 381–442.
- 22 Baxter, C. F., and Roberts, E. (1958). The γ-aminobutyric acid-α-ketoglutaric acid transaminase of beef brain. J. Biol. Chem. 233, 1135–1139.
- 23 Kanner, B. I., and Schuldiner, S. (1987). Mechanism of transport and storage of neurotransmitters. CRC Crit. Rev. Biochem. 22, 1–38.
- 24 Kavanaugh, M. P., Arriza, J., North, R. A., and Amara, S. G. (1992). Electrogenic uptake of gamma-aminobutyric acid by a cloned transporter expressed in Xenopus oocytes. J. Biol. Chem. 267, 22007–22009.
- 25 Zerangue, N., and Kavanaugh, M. P. (1996). Flux coupling in a neuronal glutamate transporter. Nature 383, 634–637.
- 26 McIntire, S. L., Reimer, R. J., Schuske, K., Edwards, R. H., and Jorgensen, E. M. (1997). Identification and characterization of the vesicular GABA transporter. Nature 389, 870–876.
- 27 Christensen, H., and Fonnum, F. (1991). Uptake of glycine, GABA and glutamate by synaptic vesicles isolated from different regions of rat CNS. Neurosci. Lett. 129, 217–220.
- 28
Sagne, C.,
El Mestikawy, S.,
Isambert, M. F.,
Hamon, M.,
Henry, J. P.,
Giros, B., and
Gasnier, B.
(1997).
Cloning of a functional GABA and glycine transporter by screening of genome database.
FEBS Lett.
417,
177–183.
10.1016/S0014-5793(97)01279-9 Google Scholar
- 29 Chaudhry, F. A., Reimer, R. J., Bellochio, E. E., Danbolt, N. C., Osen, K. K., Edwards, R. H., and Storm-Mathisen, J. (1998). The vesicular GABA transporter VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J. Neurosci. 18, 9733–9750.
- 30 Dumoulin, A., Rostaing, P., Bedet, C., Levi, S., Isambert, F., Henry, J. P., Triller, A., and Gasnier, B. (1999). Presence of the vesicular inhibitory amino acid transporter in GABAergic and glycinergic terminal boutons. J. Cell Sci. 112, 811–823.
- 31 Lopez-Corcuera, B., Liu, Q. R., Mandiyan, S., Nelson, A., and Nelson, N. (1992). Expression of a mouse brain cDNA encoding novel γ-aminobutyric acid transporter. J. Biol. Chem. 267, 17491–17493.
- 32 Borden, L. A., Smith, K. E., Hartig, P. R., Branchek, T. A., and Weinshank, R. L. (1992). Molecular heterogeneity of the γ-aminobutyric acid (GABA) transport system. J. Biol. Chem. 267, 21098–21104.
- 33 Borden, L. A., Murali, D. T. G., Smith, K. E., Weinshank, R. L., Branchek, T. A., and Gluchowski, C. (1994). Tiagabine, SK&F 89976-A, CI-966, and NCC-711 are selective for the cloned GABA transporter GAT-1. Eur. J. Pharmacol. 269, 219–224.
- 34 Clark, J. A., Deutch, A. Y., Gallipoli, P. Z., and Amara, S. (1992). Functional expression of a β-alanine-sensitive neuronal GABA transporter. Neuron 9, 337–348.
- 35 Liu, Q. R., Lopez-Corcuera, B., Mandiyan, S., Nelson, H., and Nelson, N. (1993). Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain. J. Biol. Chem. 268, 2106–2112; Erratum 268, 9156.
- 36 Yamauchi, A., Uchida, S., Kwon, H. M., Preston, A., Robey, R. B., Garcia-Perez, A., Burg, M. B., and Handler, J. S. (1992). Cloning of a Na+ and Cl−-dependent transporter that is regulated by hypertonicity. J. Biol. Chem. 267, 649–652.
- 37 Borden, L. A., Smith, K. E., Gustafson, E. L., Branchek, T. A., and Weinshank, R. L. (1995). Cloning and expression of a betaine/GABA transporter from human brain. J. Neurochem. 64, 977–984.
- 38 Radian, R., Ottersen, O. P., Storm-Mathisen, J., Castel, M., and Kanner, B. I. (1990). Immunocytochemical localization of the GABA transporter in rat brain. J. Neurosci. 10, 1319–1330.
- 39
Ribak, C. E.,
Tong, W. M., and
Brecha, N. C.
(1996).
GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus.
J. Comp. Neurol.
367,
595–606.
10.1002/(SICI)1096-9861(19960415)367:4<595::AID-CNE9>3.0.CO;2-# CAS PubMed Web of Science® Google Scholar
- 40 Gadea, A., and Lopez-Colome, A. M. (2001). Glial transporters for glutamate, glycine, and GABA: II. GABA transporters. J. Neurosci. Res. 63, 461–468.
- 41 Minelli, A., Brecha, N. C., Karschin, C., DeBiasi, S., and Conti, F. (1995). GAT-1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J. Neurosci. 15, 7734–7746.
- 42 Borden, L. A., Smith, K. E., Vaysse, P. J., Gustafson, E. L., Weinshank, R. L., and Branchek, T. A. (1995). Re-evaluation of GABA transport in neuronal and glial cell cultures: Correlation of pharmacology and mRNA localization. Receptors Channels 3, 129–146.
- 43 Yan, X. X., Cariaga, W. A., and Ribak, C. E. (1997). Immunoreactivity for GABA plasma membrane transporter, GAT-1, in the developing rat cerebral cortex: Transient presence in the somata of neocortical and hippocampal neurons. Dev. Brain Res. 99, 1–19.
- 44 Frahm, C., and Draguhn, A. (2001). GAD and GABA transporter (GAT-1) mRNA expression in the developing rat hippocampus. Dev. Brain Res. 132, 1–13.
- 45 Bel, N., Figueras, G., Vilar, M. T., Sunol, C., and Artigas, F. (1997). Antidepressant drugs inhibit a glial 5-hydroxytryptamine transporter in rat brain. Eur. J. Neurosci. 9, 1728–1738.
- 46 Yasumi, M., Sato, K., Shimada, S., Nishimura, M., and Tohyama, M. (1997). Regional distribution of GABA transporter 1 (GAT1) in the rat brain: Comparison with glutamic acid decarboxylase 67 (GAD67) mRNA localization. Mol. Brain Res. 44, 205–218.
- 47 Ikegaki, N., Saito, N., Hashima, M., and Tanaka, C. (1994). Production of specific antibodies against GABA transporter subtypes (GAT1, GAT2, GAT3) and their application in immunocytochemistry. Mol. Brain Res. 26, 47–54.
- 48 Durkin, M. M., Smith, K. E., Borden, L. A., Weinshank, R. L., Branchek, T. A., and Gustafson, E. L. (1995). Localization of messenger RNAs encoding three GABA transporters in rat: An in situ hybridization study. Mol. Brain Res. 33, 7–21.
- 49 Minelli, A., De Biasi, S., Brecha, N. C., Vitellaro, Zuccarello, L., and Conti, F. (1996). GAT-3, a high affinity GABA plasma membrane transporter, is localized to astrocytic processes, and is not confined to the vicinity of GABAergic synapses in the cerebral cortex. J. Neurosci. 16, 6255–6264.
- 50 Pietrini, G., Suh, Y. J., Edelmann, L., Rudnick, G., and Caplan, M. (1994). The axonal γ-aminobutyric acid transporter GAT1 is sorted to the apical membranes of polarized epithelial cells. J. Biol. Chem. 269, 4668–4674.
- 51 Dotti, C. G., and Simons, K. (1990). Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture. Cell 62, 63–72.
- 52 Guastella, J., Nelson, N., Nelson, H., Czyzykk, L., Leynan, S., Miedel, M. C., Davidson, N., Lester, H. A., and Kanner, B. I. (1990). Cloning and expression of a rat brain GABA transporter. Science 249, 1303–1306.
- 53 Clark, J. A. (1997). Analysis of the transmembrane topology and membrane assembly of the GAT-1 γ-aminobutyric acid transporter. J. Biol. Chem. 272, 14695–14704.
- 54 Bennett, E. R., and Kanner, B. I. (1997). The membrane topology of GAT-1, a (Na++Cl−)-coupled γ-aminobutyric acid transporter from rat brain. J. Biol. Chem. 272, 1203–1210.
- 55 Pantanowitz, S., Bendahan, A., and Kanner, B. I. (1993). Only one of the charged amino acids located in the transmembrane alpha-helices of the gamma-aminobutyric acid transporter (subtype A) is essential for its activity. J. Biol. Chem. 268, 3222–3225.
- 56 Mager, S., Kleinberger-Doron, N., Keshet, G. I., Davidson, N., Kanner, B. I., and Lester, H. A. (1996). Ion binding and permeation at the GABA transporter GAT1. J. Neurosci. 16, 5405–5414.
- 57 Chen, J. G., Sachpatzidis, A., and Rudnick, G. (1997). The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. J. Biol. Chem. 272, 28321–28327.
- 58Barker, E. L., and Blakely, R. D. (1995). Psychopharmacology: The Fourth Generation of Progress. Raven, New York, pp. 321–333.
- 59 Kanner, B. I. (2003). Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J. Biol. Chem. 278, 3705–3712.
- 60 Melamed, N., and Kanner, B. I. (2004). Transmembrane domains I and II of the γ-aminobutyric acid transporter GAT-4 contain molecular determinants of substrate specificity. Mol. Pharmacol. 65, 1452–1461.
- 61 Scholze, P., Freissmuth, M., and Sitte, H. H. (2002). Mutations within an intramembrane leucine heptad repeat disrupt oligomer formation of the rat GABA transporter 1. J. Biol. Chem. 277, 43682–43690.
- 62 Sipila, S., Huttu, K., Voipio, J., and Kaila, K. (2004). GABA uptake via GABA transporter-1 modulates GABAergic transmission in the immature hippocampus. J. Neurosci. 24, 5877–5880.
- 63 Feller, M. B. (1999). Spontaneous correlated activity in developing neural circuits. Neuron 22, 653–656.
- 64 Penn, A. A., and Shatz, C. J. (1999). Brain waves and brain wiring: The role of endogenous and sensory-driven neural activity in development. Pediatr. Res. 45, 447–458.
- 65 Katz, L. C., and Crowley, J. C. (2002). Development of cortical circuits: Lessons from ocular dominance columns. Nat. Rev. Neurosci. 3, 34–42.
- 66
Evans, J. E.,
Frostholm, A., and
Rotter, A.
(1996).
Embryonic and postnatal expression of four gamma-aminobutyric acid transporter mRNAs in the mouse brain and leptomeninges.
J. Comp. Neurol.
376,
431–446.
10.1002/(SICI)1096-9861(19961216)376:3<431::AID-CNE6>3.0.CO;2-3 CAS PubMed Web of Science® Google Scholar
- 67 Takanaga, H., Ohtsuki, S., Hosoya, K., and Terasaki, T. (2001). GAT2/BGT-1 as a system responsible for the transport of gamma-aminobutyric acid at the mouse blood-brain barrier. J. Cereb. Blood Flow Metabol. 21, 1232–1239.
- 68 Gomeza, J., Gimenez, C., and Zafra, F. (1994). Cellular distribution and regulation by cAMP of the GABA transporter. Mol. Brain Res. 21, 150–156.
- 69 Gomeza, J., Casado, M., Gimenez, C., and Aragon, C. (1991). Inhibition of high-affinity γ-aminobutyric acid uptake in primary astrocyte cultures by phorbol esters and phospholipase C. J. Biochem. 275, 435–439.
- 70 Corey, J. L., Davidson, N., Lester, H. A., Brecha, N., and Quick, M. W. (1994). Protein kinase C modulates the activity of a cloned gamma-aminobutyric acid transporter expressed in Xenopus oocytes via regulated subcellular redistribution of the transporter. J. Biol. Chem. 269, 14759–14767.
- 71 Quick, M. W., Corey, J. L., Davidson, N., and Lester, H. (1997). Second messengers trafficking-related proteins and amino acid residues that contribute to the functional regulation of the rat brain GABA transporter GAT1. J. Neurosci. 17, 2967–2979.
- 72 French, J. A., Kanner, A. M., Bautista, J., Abou-Khalil, B., Browne, T., Harden, C. L., Theodore, W. H., Bazil, C., Stern, J., Schachter, S. C., Bergen, D., Hirtz, D., Montouris, G. D., Nespeca, M., Gidal, B., Marks, W. J., Jr., Turk, W. R., Fischer, J. H., Bourgeois, B., Wilner, A., Faught, R. E., Jr., Sachdeo, R. C., Beydoun, A., and Glauser, T. A., 2004. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 62, 1261–1273.
- 73 Borden, L. A. (1996). GABA transporter heterogeneity: Pharmacology and cellular localization. Neurochem. Int. 29, 335–356.
- 74 Clark, J. A., and Amara, S. G. (1994). Stable expression of a neuronal gammaaminobutyric acid transporter, GAT-3, in mammalian cells demontrates unique pharmacological properties and ion dependence. Mol. Pharmacol. 46, 550–557.
- 75 Dhar, T. G., Borden, L. A., Tyagarajan, S., Smith, K. E., Branchek, T. A., Weinshank, R. L., and Gluchowski, C. (1994). Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: Identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3. J. Med. Chem. 37, 2334–2342.
- 76 Dalby, N. O., Thomsen, C., Fink-Jensen, A., Lundbeck, J., Sokilde, B., Ming-Man, C., Sorensen, P. O., and Meldrum, B. (1997). Anticonvulsant properties of two GABA uptake inhibitors NNC 05–2045 and NNC 05–2090, not acting preferentially on GAT1. Epilepsy Res. 28, 51–61.
- 77 Takeuchi, A., and Onodera, K. (1972). Effect of bicuculline on the GABA receptor of the crayfish neuromuscular junction. Nat. New Biol. 236, 55–56.
- 78 Takeuchi, A., and Takeuchi, N. (1969). A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish. J. Physiol. 205, 377–391.
- 79 Takeuchi, A., and Takeuchi, N. (1967). Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction. J. Physiol. 191, 575–590.
- 80 Hill, D. R., and Bowery, N. G. (1981). 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain. Nature 290, 149–152.
- 81 Drew, C. A., Johnston, G. A., and Weatherby, R. P. (1984). Bicuculline-insensitive GABA receptors: Studies on the binding of (β)-baclofen to rat cerebellar membranes. Neurosci. Lett. 52, 317–321.
- 82 Zhang, D., Pan, Z. H., Awobuluyi, M., and Lipton, S. A. (2001). Structure and function of GABAC receptors: A comparison of native versus recombinant receptors. Trends Pharmacol. Sci. 22, 121–132.
- 83 Feigenspan, A., Wassle, H., and Bormann, J. (1993). Pharmacology of GABA receptor Cl− channels in rat retinal bipolar cells. Nature 361, 159–162.
- 84 Qian, H., and Dowling, J. E. (1993). Novel GABA responses from rod-driven retinal horizontal cells. Nature 361, 162–164.
- 85 Lukasiewicz, P. D. (1996). GABAC receptors in the vertebrate retina. Mol. Neurobiol. 12, 181–194.
- 86 Wegelius, K., Pasternack, M., Hiltunen, J. O., River, C., Kaila, K., Saarma, M., and Reeben, M. (1998). Distribution of GABA receptor rho subunit transcripts in the rat brain. Eur. J. Neurosci. 10, 350–357.
- 87 Barnard, E. A., Skolnick, P., Olsen, R. W., Mohler, H., Sieghart, W., Biggio, G., Braestrup, C., Bateson, A. N., and Langer, S. Z. (1998). International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: Classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50, 291–313.
- 88 Emberger, W., Windpassinger, C., Petek, E., Kroisel, P. M., and Wagner, K. (2000). Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenet. Cell Genet. 89, 281–282.
- 89 Dean, M., Lucas-Derse, S., Bolos, A., O'Brien, S. J., Kirkness, E. F., Fraser, C. M., and Goldman, D. (1991). Genetic mapping of the beta 1 GABA receptor gene to human chromosome 4, using a tetranucleotide repeat polymorphism. Am. J. Hum. Genet. 49, 621–626.
- 90 Wilcox, A. S., Warrington, J. A., Gardiner, K., Berger, R., Whiting, P., Altherr, M. R., Wasmuth, J. J., Patterson, D., and Sikela, J. M. (1992). Human chromosomal localization of genes encoding the γ1 and γ2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome. Proc. Nat. Acad. Sci. USA 89, 5857–5861.
- 91 Wilke, K., Gaul, R., Klauck, S. M., and Poustka, A. (1997). A gene in human chromosome band Xq28 (GABRE) defines a putative new subunit class of the GABAA neurotransmitter receptor. Genomics 45, 1–10.
- 92 Johnson, K. J., Sander, T., Hicks, A. A., van Marle, A., Janz, D., Mullan, M. J., Riley, B. P., and Darlison, M. G. (1992). Confirmation of the localization of the human GABAA receptor alpha 1-subunit gene (GABRA1) to distal 5q by linkage analysis. Genomics 14, 745–748.
- 93 Hicks, A. A., Bailey, M. E., Riley, B. P., Kamphuis, W., Siciliano, M. J., Johnson, K. J., and Darlison, M. G. (1994). Further evidence for clustering of human GABAA receptor subunit genes: Localization of the alpha 6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis. Genomics 20, 285–288.
- 94 Hedblom, E., and Kirkness, E. F. (1997). A novel class of GABAA receptor subunit in tissues of the reproductive system. J. Biol. Chem. 272, 15346–15350.
- 95 Cutting, G. R., Lu, L., O'Hara, B. F., Kasch, L. M., Montrose-Rafizadeh, C., Donovan, D. M., Shimada, S., Antonarakis, S. E., Guggino, W. B., Uhl, G. R., and Kazazian, H. H., Jr. (1991). Cloning of the γ-aminobutyric acid (GABA) rho1 cDNA: A GABA receptor subunit highly expressed in the retina. Proc. Nat. Acad. Sci. USA 88, 2673–2677.
- 96 Glatt, K., Glatt, H., and Lalande, M. (1997). Structure and organization of GABRB3 and GABRA5. Genomics 41, 63–69. Erratum 44, 155.
- 97 Glatt, K. A., Sinnett, D., and Lalande, M. (1992). Dinucleotide repeat polymorphism at the GABAA receptor alpha 5 (GABRA5) locus at chromosome 15q11-q13. Hum. Mol. Genet. 1, 348.
- 98 Sinnett, D., Wagstaff, J., Glatt, K., Woolf, E., Kirkness, E. J., and Lalande, M. (1993). High-resolution mapping of the gamma-aminobutyric acid receptor subunit β3 and α5 gene cluster on chromosome 15q11-q13, and localization of breakpoints in two Angelman syndrome patients. Am. J. Hum. Genet. 52, 1216–1229.
- 99 Greger, V., Knoll, J. H., Woolf, E., Glatt, K., Tyndale, R. F., DeLorey, T. M., Olsen, R. W., Tobin, A. J., Sikela, J. M., and Nakatsu, Y. (1995). The gamma-aminobutyric acid receptor gamma 3 subunit gene (GABRG3) is tightly linked to the alpha 5 subunit gene (GABRA5) on human chromosome 15q11-q13 and is transcribed in the same orientation. Genomics 26, 258–264.
- 100 Hadingham, K. L., Wingrove, P., Le Bourdelles, B., Palmer, K. J., Ragan, C. I., and Whiting, P. J. (1993). Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant α1, α2, α3, and α5 containing human gamma-aminobutyric acidA receptors. Mol. Pharmacol. 43, 970–975.
- 101 Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J., Brown, N., Wafford, K. A., and Whiting, P. J. (1999). Theta, a novel gamma-Aminobutyric acid type A receptor subunit. Proc. Nat. Acad. Sci. USA 96, 9891–9896.
- 102 Sinkkonen, S. T., Hanna, M. C., Kirkness, E. F., and Korpi, E. R. (2000). GABAA receptor epsilon and theta subunits display unusual structural variation between species and are enriched in the rat locus ceruleus. J. Neurosci. 20, 3588–3595.
- 103 Shimada, S., Cutting, G. R., and Uhl, G. R. (1992). γ-Aminobutyric acid A or C receptor? γ-Aminobutyric acid ρ1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive γ-aminobutyric acid responses in Xenopus oocytes. Mol. Pharmacol. 41, 683–687.
- 104 Kusama, T., Spivak, C. E., Whiting, P., Dawson, V. L., Schaeffer, J. C., and Uhl, G. R. (1993). Pharmacology of GABAρ1 and GABAα/β receptors expressed in Xenopus oocytes and Cos cells. Br. J. Pharmacol. 109, 200–206.
- 105 Kusama, T., Wang, T. L., Guggino, W. B., Cutting, G. R., and Uhl, G. R. (1993). GABA rho2 receptor pharmacological profile: GABA recognition site similarities to rho1. Eur. J. Pharmacol. 245, 83–84.
- 106 Hervers, W., and Luddens, H. (1998). The diversity of GABAA receptors. Mol. Neurobiol. 18, 35–86.
- 107 Sieghart, W., and Sperk, G. (2002). Subunit composition, distribution and function of GABAA receptor subtypes. Curr. Top. Med. Chem. 2, 795–816.
- 108 Ben-Ari, Y., Khazipov, R., Leinekugel, X., Caillard, O., and Galarsa, J. L. (1997). GABAA, NMDA and AMPA receptors: A developmentally regulated “menage a trois.” Trends Neurosci. 20, 523–529.
- 109 Taketo, M., and Yoshioka, T. (2000). Developmental change of GABAA receptor-mediated current in rat hippocampus. Neuroscience 96, 507–514.
- 110 Rivera, C., Voipio, J., Payne, J. A., Ruusuvuori, E., Lahtinen, H., Lamsa, K., Pirvola, U., Saarma, M., and Kaila, K. (1999). The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255.
- 111 Tomiko, S. A., Taraskevich, P. S., and Douglas, W. W. (1983). GABA acts directly on cells of pituitary pars intermedia. Nature 301, 706–707.
- 112 Cherubini, E., Giairsa, J. L., and Ben-Ari, Y. (1991). GABA, an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519.
- 113 Lamsa, K., and Taira, T. (2003). Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area. J. Neurophysiol. 90, 1983–1995.
- 114 Timofeev, I., Grenier, F., and Steriade, M. (2002). The role of chloride-dependent inhibition and the activity of fast-spiking neurons during cortical spike-wave electrographic seizures. Neuroscience 114, 1115–1132.
- 114a Bettler, B. and Tiao, J. Y. (2006) Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol. Ther. 110, 533–543.
- 116 Bowery, N. G., Hill, D. R., Hudson, A. L., Doble, A., Middlemiss, D. N., Shaw, J., and Turnbull, M. (1980). (−)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283, 92–94.
- 117Bein, H. J. (1972). In Spasticity: A Topical Survey. ( W. Birkmayer, ed.) Hans Huber, Vienna, pp. 76–89.
- 118Keberle, H., and Faigle, J. W. (1972). In Spasticity: A Topical Survey ( W. Birkmayer, ed.) Hans Huber, Vienna, pp. 90–100.
- 119 Moragues, N., Ciofi, P., Lafon, P., Odessa, M. F., Tramu, G., and Garret, M. (2000). cDNA cloning and expression of a gamma-aminobutyric acid A receptor epsilon-subunit in rat brain. Eur. J. Neurosci. 12, 4318–4330.
- 120 Bateson, A. N., Lasham, A., and Darlison, M. G. (1991). γ-aminobutyric acidA receptor heterogeneity is increased by alternative splicing of a novel beta-subunit gene transcript. J. Neurochem. 56, 1437–1440.
- 121 Levin, M. L., Chatterjee, A., Pragliola, A., Worley, K. C., Wehnert, M., Zhuchenko, O., Smith, R. F., Lee, C. C., and Herman, G. E. (1996). A comparative transcription map of the murine bare patches (Bpa) and striated (Str) critical regions and human Xq28. Genome Res. 6, 465–477.
- 122 Whiting, P., McKernan, R. M., and Iversen, L. L. (1990). Another mechanism for creating diversity in γ-aminobutyrate type A receptors: RNA splicing directs expression of two forms of γ2 subunit, one of which contains a protein kinase C phosphorylation site. Proc. Nat. Acad. Sci. USA 87, 9966–9967.
- 123 Kofuji, P., Wang, J. B., Moss, S. J., Huganir, R. L., and Burt, D. R. (1991). Generation of two forms of the gamma-aminobutyric acid-A receptor γ2 subunit in mice by alternative splicing. J. Neurochem. 56, 713–715.
- 124 Harvey, R. J., Chinchetru, M. A., and Darlison, M. G. D. (1994). Alternative splicing of a 51-nucleotide exon that encodes a putative protein kinase C phosphorylation site generates two forms of the chicken γ-aminobutyric acidA receptor β2 subunit. J. Neurochem. 62, 10–16.
- 125 Kirkness, E. F., and Fraser, C. M. (1993). A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor beta3 subunit (GABRB3). J. Biol. Chem. 268, 4420–4428.
- 126 Korpi, E. R., Kuner, T., Kristo, P., Kohcer, M., Herb, A., Luddens, H., and Seeburg, P. H. (1994). Small N-terminal deletion by splicing in cerebellar α6-subunit abolishes GABAA receptor function. J. Neurochem. 63, 1167–1170.
- 127 Schofield, P. R., Darlison, M. G., Fujita, N., Burt, D. R., Stephenson, F. A., Rodriguez, H., Rhee, L. M., Ramachandran, J., Reale, V., Glencorse, T. A., Seeburg, P. H., and Barnard, E. A. (1987). Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor superfamily. Nature 328, 221–227.
- 128 Buller, A. L., Hastings, G. A., Kirkness, E. F., and Fraser, C. M. (1994). Site-directed mutagenesis of N-linked glycosylation sites on the gamma-aminobutyric acid type A receptor alpha 1 subunit. Mol. Pharmacol. 46, 858–865.
- 129 Xu, M., and Akabas, M. H. (1996). Identification of channel-lining residues in the M2 membrane-spanning segment of the GABAA receptor α1 subunit. J. Gen. Physiol. 107, 195–205.
- 130 Williams, D. B., and Akabas, M. H. (2001). Evidence for distinct conformations of the two alpha 1 subunits in diazepam-bound GABAA receptors. Neuropharmacology 41, 539–545.
- 131 Goren, E. N., Reeves, D. C., and Akabas, M. H. (2004). Loose protein packing around the extracellular half of the GABAA receptor beta 1 subunit M2 channel-lining segment. J. Biol. Chem. 279, 11198–11205.
- 132 Laurie, D. J., Seeburg, P. H., and Wisden, W. (1992). The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J. Neurosci. 12, 1063–1076.
- 133 Persohn, E., Malherbe, P., and Richards, J. G. (1992). Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS. J. Comp. Neurol. 326, 193–216.
- 134 Wisden, W., and Seeburg, P. H. (1992). GABAA receptor channels: From subunits to functional entities. Curr. Opin. Neurobiol. 2, 263–269.
- 135 Miralles, C. P., Gutierrez, A., Khan, Z. U., Vitorica, J., and De Blas, A. L. (1994). Differential expression of the short and long forms of the γ2 subunit of the GABAA/benzodiazepine receptors. Mol. Brain Res. 24, 129–139.
- 136 Kultas-Ilinsky, K., Leontiev, V., and Whiting, P. J. (1998). Expression of 10 GABAA receptor subunit messenger RNAs in the motor-related thalamic nuclei and basal ganglia of Macaca mulatta studied with in situ hybridization histochemistry. Neuroscience 85, 179–204.
- 137 Benke, D., Mertens, S., Trzeciak, A., Gillessen, D., and Mohler, H. (1991). Identification and immunohistochemical mapping of GABAA receptor subtypes containing the delta-subunit in rat brain. FEBS Lett. 283, 145–149.
- 138 Benke, D., Mertens, S., Trzeciak, A., Gillessen, D., and Mohler, H. (1991). GABAA receptors display association of γ2 subunit with α1 and β2/3 subunits. J. Biol. Chem. 266, 4478–4483.
- 139 Benke, D., Cicin-Sain, A., Mertens, S., and Mohler, H. (1991). Immunochemical identification of the α1 and α3 subunits of the GABAA-receptor in rat brain. J. Receptor Res. 11, 407–424.
- 140 Fritschy, J. M., Benke, D., Mertens, S., Oertel, W. H., Bachi, T., and Mohler, H. (1992). Five subtypes of type A γ-aminobutyric acid receptors identified in neurons by double and triple immunofluorescence staining with subunit-specific antibodies. Proc. Nat. Acad. Sci. USA 89, 6726–6730.
- 141 Fritschy, J. M., and Mohler, H. (1995). GABAA-receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194.
- 142
Fritschy, J. M.,
Weinmann, O.,
Wenzel, A., and
Benke, D.
(1998).
Synapse-specific localization of NMDA and GABAA receptor subunits revealed by antigen-retrieval immunohistochemistry.
J. Comp. Neurol.
390,
194–210.
10.1002/(SICI)1096-9861(19980112)390:2<194::AID-CNE3>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 143 Gutierrez, A., Khan, Z. U., and De Blas, A. L. (1994). Immunocytochemical localization of γ2 short and γ2 long subunits of the GABAA receptor in the rat brain. J. Neurosci. 4, 7168–7179.
- 144 Sperk, G., Schwarzer, C., Tsunashima, K., Fuchs, K., and Sieghart, W. (1997). GABAA receptor subunits in the rat hippocampus I: Immunocytochemical distribution of 13 subunits. Neuroscience 80, 987–1000.
- 145 Moragues, N., Ciofi, P., Tramu, G., and Garret, M. (2002). Localisation of GABAA receptor epsilon-subunit in cholinergic and aminergic neurones and evidence for co-distribution with the theta-subunit in rat brain. Neuroscience 111, 657–669.
- 146 Moragues, N., Ciofi, P., Lafon, P., Tramu, G., and Garret, M. (2003). GABAA receptor epsilon subunit expression in identified peptidergic neurons of the rat hypothalamus. Brain Res. 967, 285–289.
- 147 Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., and Sperk, G. (2000). GABAA receptors: Immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815–850.
- 148 Schwarzer, C., Berresheim, U., Pirker, S., Wieselthaler, A., Fuchs, K., Sieghart, W., and Sperk, G. (2001). Distribution of the major gamma-aminobutyric acidA receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J. Comp. Neurol. 433, 526–549.
- 149 Poltl, A., Hauer, B., Fuchs, K., Tretter, V., and Sieghart, W. (2003). Subunit composition and quantitative importance of GABAA receptor subtypes in the cerebellum of mouse and rat. J. Neurochem. 87, 1444–1455.
- 150 Benke, D., Fritschy, J. M., Trzeciak, A., Bannerworth, W., and Mohler, H. (1994). Distribution, prevalence and drug-binding profile of GABAA-receptor subtypes differing in β-subunit isoform. J. Biol. Chem. 269, 27100–27107.
- 151 Benke, D., Honer, M., Michel, C., and Mohler, H. (1996). GABAA receptor subtypes differentiated by their gamma-subunit variants: Prevalence, pharmacology and subunit architecture. Neuropharmacology 35, 1413–1423.
- 152 Gao, B., and Fritschy, J. M. (1994). Selective allocation of GABAA receptors containing the α1 subunit to neurochemically distinct subpopulations of rat hippocampal interneurons. Eur. J. Neurosci. 6, 837–853.
- 153 Gao, B., Hornung, J. P., and Fritschy, J. M. (1995). Identification of distinct GABAA-receptor subtypes in cholinergic and parvalbumin-positive neurons of the rat and marmoset medial septum-diagonal band complex. Neuroscience 65, 101–117.
- 154 Benke, D., Michel, C., and Mohler, H. (1997). GABAA receptors containing the alpha4-subunit: Prevalence, distribution, pharmacology, and subunit architecture in situ. J. Neurochem. 69, 806–814.
- 155 Santi, M. R., Vincini, S., Eldalah, B., and Neale, J. H. (1994). Analysis by polymerase chain reaction of alpha 1 and alpha 6 GABAA receptor subunit mRNAs in individual cerebellar neurons after whole-cell recordings. J. Neurochem. 63, 2357–2360.
- 156 Wisden, W., Laurie, D. J., Monyer, H., and Seeburg, P. H. (1992). The distribution of 13 GABA receptor subunit mRNAs in the rat brain: I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 12, 1040–1062.
- 157 Li, M., and De Blas, A. L. (1997). Coexistence of two β subunit isoforms in the same γ-aminobutyric acid type A receptor. J. Biol. Chem. 272, 16564–16569.
- 158 Somogyi, P., Fritschy, J. M., Benke, D., Roberts, J. D., and Sieghart, W. (1996). The γ2 subunit of the GABAA receptor is concentrated in synaptic junctions containing the α1 and β2/3 subunits in hippocampus, cerebellum, and globus pallidus. Neuropharmacology 35, 1425–1444.
- 159 Sur, C., Farrar, S. J., Kerby, J., Whiting, P. J., Atack, J. R., and McKernan, R. M. (1999). Preferential coassembly of α4 and δ subunits of the gamma-aminobutyric acidA receptor in rat thalamus. Mol. Pharmacol. 56, 110–115.
- 160 Bencsits, E., Ebert, V., Tretter, V., and Sieghart, W. (1999). A significant part of native gamma-aminobutyric AcidA receptors containing alpha4 subunits do not contain gamma or delta subunits. J. Biol. Chem. 274, 19613–19616.
- 161 Didelon, F., Mladinic, M., Cherubini, E., and Bradbury, A. (2000). Early expression of GABAA receptor delta subunit in the neonatal rat hippocampus. J. Neurosci. Res. 62, 638–643.
- 162 Didelon, F., Sciancalepore, M., Savic, N., Mladinic, M., Bradbury, A., and Cherubini, E. (2002). gamma-aminobutyric acidA rho receptor subunits in the developing rat hippocampus. J. Neurosci. Res. 67, 739–744.
- 163 Neelands, T. R., Fisher, J. L., Bianchi, M., and Macdonald, R. (1999). Spontaneous and gamma-aminobutyric acid GABA-activated GABAA receptor channels formed by epsilon subunit-containing isoforms. Mol. Pharmacol. 55, 168–178.
- 164 Enz, R., Brandstatter, J. H., Hartveit, E., Wassle, H., and Bormann, J. (1995). Expression of GABA receptor ρ1 and ρ2 subunits in the retina and brain of the rat. Eur. J. Neurosci. 7, 1495–1501.
- 165 Koulen, P., Brandstatter, J. H., Enz, R., Bormann, J., and Wassle, H. (1998). Synaptic clustering of GABAC receptor ρ-subunits in the rat retina. Eur. J. Neurosci. 10, 115–127.
- 166
Koulen, P.
(1999).
Postnatal development of GABAA receptor β1, β2/3, and γ2 immunoreactivity in the rat retina.
J. Neurosci. Res.
57,
185–194.
10.1002/(SICI)1097-4547(19990715)57:2<185::AID-JNR4>3.0.CO;2-T CAS PubMed Web of Science® Google Scholar
- 167
Fletcher, E. L.,
Koulen, P., and
Wassle, H.
(1998).
GABAA and GABAC receptors on mammalian rod bipolar cells.
J. Comp. Neurol.
396,
351–365.
10.1002/(SICI)1096-9861(19980706)396:3<351::AID-CNE6>3.0.CO;2-1 CAS PubMed Web of Science® Google Scholar
- 168 Sur, C., Wafford, K. A., Reynolds, D. S., Hadingham, K. L., Bromidge, F., Macaulay, A., Collinson, N., O'Meara, G., Howell, O., Newman, R., Myers, J., Atack, J. R., Dawson, G. R., McKernan, R. M., Whiting, P. J., and Rosahl, T. W. (2001). Loss of the major GABAA receptor subtype in the brain is not lethal in mice. J. Neurosci. 21, 3409–3418.
- 169 Boue-Grabot, E., Roudbaraki, M., Bascles, L., Tramu, G., Bloch, B., and Garret, M. (1998). Expression of GABA receptor rho subunits in rat brain. J. Neurochem. 70, 899–907.
- 170 Drew, C. A., and Johnston, G. A. (1992). Bicuculline- and baclofen-insensitive gamma-aminobutyric acid binding to rat cerebellar membranes. J. Neurochem. 58, 1087–1092.
- 171 Arakawa, T., and Okada, Y. (1988). Excitatory and inhibitory action of GABA on synaptic transmission in slices of guinea pig superior colliculus. Eur. J. Pharmacol. 158, 217–224.
- 172 Clark, S. E., Garret, M., and Platt, B. (2001). Postnatal alterations of GABA receptor profiles in the rat superior colliculus. Neuroscience 104, 441–454.
- 173 Delaney, A. J., and Sah, P. (1999). GABA receptors inhibited by benzodiazepines mediate fast inhibitory transmission in the central amygdala. J. Neurosci. 19, 9698–9704.
- 174 Cherubini, E., Martina, M., Sciancalepore, M., and Strata, F. (1998). GABA excites immature CA3 pyramidal cells through bicuculline-sensitive and -insensitive chloride-dependent receptors. Perspect. Dev. Neurobiol. 5, 289–304.
- 175 Martina, M., Mozrzymas, J. W., Strata, F., and Cherubini, E. (1996). Zinc modulation of bicuculline-sensitive and -insensitive GABA receptors in the developing rat hippocampus. Eur. J. Neurosci. 8, 2168–2176.
- 176 Zhu, J. J., and Lo, F. S. (1999). Three GABA receptor-mediated postsynaptic potentials in interneurons in the rat lateral geniculate nucleus. J. Neurosci. 19, 5721–5730.
- 177 Park, J. S., Higashi, H., Nagata, K., and Yoshimura, M. (1999). Bicuculline-resistant, Cl− dependent GABA response in the rat spinal dorsal horn. Neurosci. Res. 33, 261–268.
- 178 Benke, D., Mertens, S., Trezciak, A., Gillessen, D., and Mohler, H. (1990). Identification of the γ2 subunit protein in native GABAA receptors in brain. Eur. J. Pharmacol. 189, 337–340.
- 179 Caruncho, H. J., and Costa, E. (1994). Double-immunolabelling analysis of GABAA receptor subunits in label-fracture replicas of cultured rat cerebellar granule cells. Receptors Channels 2, 143–153.
- 180 Bohlhalter, S., Weinmann, O., Mohler, H., and Fritschy, J. M. (1996). Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord: An immunohistochemical study. J. Neurosci. 16, 283–297.
- 181
Fujiyama, F.,
Fritschy, J. M.,
Stephenson, F. A., and
Bolam, J. P.
(2000).
Synaptic localization of GABAA receptor subunits in the striatum of the rat.
J. Comp. Neurobiol.
416,
158–172.
10.1002/(SICI)1096-9861(20000110)416:2<158::AID-CNE3>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- 182 Nusser, Z., Roberts, J. D., Baude, A., Richards, J. G., and Somogyi, P. (1995). Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method. J. Neurosci. 15, 2948–2960.
- 183 Nusser, Z., Roberts, J. D., Baude, A., Richards, J. G., Sieghart, W., and Somogyi, P. (1995). Immunocytochemical localization of the α1 and β2/3 subunits of the GABAA receptor in relation to specific GABAergic synapses in the dentate gyrus. Eur. J. Neurosci. 7, 630–646.
- 184 Nusser, Z., Sieghart, W., Stephenson, F. A., and Somogyi, P. (1996). The α6 subunit of the GABAA receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells. J. Neurosci. 16, 103–114.
- 185 Nusser, Z., Sieghart, W., Benke, D., Fritschy, J. M., and Somogyi, P. (1996). Differential synaptic localization of two major gamma-aminobutyric acid type A receptor alpha subunits on hippocampal pyramidal cells. Proc. Nat. Acad. Sci. USA 93, 11939–11944.
- 186 Todd, A. J., Watt, C., Spike, R. C., and Sieghart, W. (1996). Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord. J. Neurosci. 16, 974–982.
- 187 Nusser, Z., Sieghart, W., and Somogyi, P. (1998). Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18, 1693–1703.
- 188 Nusser, Z., Ahmad, Z., Tretter, V., Fuchs, K., Wisden, W., Sieghart, W., and Somogyi, P. (1999). Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene. Eur. J. Neurosci. 11, 1685–1697.
- 189 Saxena, N. C., and Macdonald, R. L. (1996). Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. Mol. Pharmacol. 49, 567–579.
- 190 Mody, I. (2001). Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem. Res. 26, 907–913.
- 191 Saxena, N. C., and MacDonald, R. L. (1994). Assembly of GABAA receptor subunits: Role of the δ-subunit. J. Neurosci. 14, 7077–7086.
- 192 Wei, W., Zhang, N., Peng, Z., Houser, C. R., and Mody, I. (2003). Perisynaptic localization of delta subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J. Neurosci. 23, 10650–10661.
- 193 Rossi, D. J., and Hamann, M. (1998). Spillover-mediated transmission at inhibitory synapses promoted by high affinity α6 subunit GABAA receptors and glomerular geometry. Neuron 20, 783–795.
- 194 Brickley, S. G., Cull-Candy, S. G., and Farrant, M. (1999). Single-channel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor subtypes. J. Neurosci. 19, 2960–2973.
- 195 Stell, B. M., and Mody, I. (2002). Receptors with different affinities mediate phasic and tonic GABAA conductances in hippocampal neurons. J. Neurosci. 22, RC223.
- 196 Yeung, J. Y., Canning, K. J., Zhu, G., Pennefather, P., MacDonald, J. F., and Orser, B. A. (2003). Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol. Pharmacol. 63, 2–8.
- 197 Banks, M. I., and Pearce, R. A. (2000). Kinetic differences between synaptic and extrasynaptic GABAA receptors in CA1 pyramidal cells. J. Neurosci. 20, 937–948.
- 198 Semyanov, A., Walker, M. C., and Kullmann, D. M. (2003). GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6, 484–490.
- 199 Adkins, C. E., Pillai, G. V., Kerby, J., Bonnert, T. P., Haldon, C., McKernan, R. M., Gonzalez, J. E., Oades, K., Whiting, P. J., and Simpson, P. B. (2001). α4β3δ GABAA receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential. J. Biol. Chem. 276, 38934–38939.
- 200 Stell, B. M., Brickley, S. G., Tang, C. Y., Farrant, M., and Mody, I. (2003). Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc. Nat. Acad. Sci. USA 100, 14439–14444.
- 201 Brunig, I., Scotti, E., Sidler, C., and Fritschy, J. M. (2002). Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J. Comp. Neurol. 443, 43–55.
- 202 Semyanov, A., Walker, M. C., Kullmann, D. M., and Silver, R. A. (2004). Tonically active GABAA receptors: Modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269.
- 203 Kullmann, D. M., Ruiz, A., Rusakov, D. M., Scott, R., Semyanov, A., and Walker, M. C. (2005). Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: Where and why? Prog. Biophys. Mol. Biol. 87, 33–46.
- 204 Dudel, J., and Kuffler, S. W. (1961). Presynaptic inhibition at the crayfish neuromuscular junction. J. Physiol. 155, 543–562.
- 205 Eccles, J. C., Schmidt, R. F., and Willis, W. D. (1963). Pharmacological studies of presynaptic inhibition. J. Physiol. 168, 500–530.
- 206 Frank, K., and Fuortes, M. G. F. (1957). Presynaptic and post synaptic inhibition of monosynaptic reflexes. Fed. Proc. 16, 39–40.
- 207 MacDermott, A. B., Role, L. W., and Siegelbaum, S. A. (1999). Presynaptic ionotropic receptors and the control of transmitter release. Annu. Rev. Neurosci. 22, 443–485.
- 208 Turecek, R., and Trussell, L. O. (2001). Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse. Nature 411, 587–590.
- 209 Turecek, R., and Trussell, L. O. (2002). Reciprocal developmental regulation of presynaptic ionotropic receptors. Proc. Nat. Acad. Sci. USA 99, 13884–13889.
- 210 Smith, T. C., and Jahr, C. E. (2002). Self-inhibition of olfactory bulb neurons. Nat. Neurosci. 5, 760–766.
- 211 Ruiz, A., Fabian-Fine, R., Scott, R., Walker, M. C., Rusakov, D. A., and Kullmann, D. M. (2003). GABAA receptors at hippocampal mossy fibers. Neuron 39, 961–973.
- 212 Rudomin, P., Engberg, I., and Jimenez, I. (1981). Mechanisms involved in presynaptic depolarization of group I and rubrospinal fibers in cat spinal cord. J. Neurophysiol. 46, 532–548.
- 213 Engelman, H. S., and MacDermott, A. B. (2004). Presynaptic ionotropic receptors and control of transmitter release. Nat. Rev. Neurosci. 5, 135–145.
- 214 Segev, I. (1990). Computer study of presynaptic inhibition controlling the spread of action potentials into axonal terminals. J. Neurophysiol. 63, 987–998.
- 215 Graham, B., and Redman, S. (1994). A simulation of action potentials in synaptic boutons during presynaptic inhibition. J. Neurophysiol. 71, 538–549.
- 216 Cattaert, D., and El Manira, A. (1999). Shunting versus inactivation: Analysis of presynaptic inhibitory mechanisms in primary afferents of the crayfish. J. Neurosci. 19, 6079–6089.
- 217 Panzanelli, P., Homanics, G. E., Ottersen, O. P., Fritschy, J. M., and Sassoe-Pognetto, M. (2004). Pre- and postsynaptic GABA receptors at reciprocal dendrodendritic synapses in the olfactory bulb. Eur. J. Neurosci. 20, 2945–2952.
- 218 Feinstein, N., Fritschy, J. M., and Parnas, I. (2003). Presynaptic membrane of inhibitory crayfish axon terminals is stained by antibodies raised against mammalian GABAA receptor subunits α3 and β2/3. J. Comp. Neurol. 465, 250–262.
- 219 Banks, M. I., Li, T. B., and Pearce, R. A. (1998). The synaptic basis of GABAA, show. J. Neurosci. 18, 1305–1317.
- 220 Hajos, N., Nusser, Z., Rancz, E. A., Freund, T. F., and Mody, I. (2000). Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy. Eur. J. Neurosci. 12, 810–818.
- 221 Klausberger, T., Roberts, J. D., and Somogyi, P. (2002). Cell type- and input-specific differences in the number and subtypes of synaptic GABAA receptors in the hippocampus. J. Neurosci. 22, 2513–2521.
- 222 Toyoshima, C., and Unwin, N. (1988). Ion channel of acetylcholine receptor reconstructed from images of postsynaptic membranes. Nature 336, 247–250.
- 223 Unwin, N. (1993). Neurotransmitter action: Opening of ligand-gated ion channels. Cell 72, 31–41.
- 224 Miyazawa, A., Fujiyoshi, Y., Stowell, M., and Unwin, N. (1999). Nicotinic acetylcholine receptor at 4.6 Å resolution: Transverse tunnels in the channel wall. J. Mol. Biol. 288, 765–786.
- 225 Unwin, N. (2003). Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy. FEBS Lett. 555, 91–95.
- 226 Nayeem, N., Green, T. P., Martin, I. L., and Barnard, E. A. (1994). Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis. J. Neurochem. 62, 815–818.
- 227 Mamalaki, C., Barnard, E. A., and Stephenson, F. A. (1989). Molecular size of the gamma-aminobutyric acidA receptor purified from mammalian cerebral cortex. J. Neurochem. 52, 124–134.
- 228 Tretter, V., Ehya, N., Fuchs, K., and Sieghart, W. (1997). Stoichiometry and assembly of a recombinant GABAA receptor subtype. J. Neurosci. 17, 2728–2737.
- 229 Backus, K. H., Arigoni, M., Drescher, U., Scheurer, L., Malherbe, P., Mohler, H., and Benson, J. A. (1993). Stoichiometry of a recombinant GABAA-receptor deduced from mutation-induced rectification. Neuroreport 5, 285–288.
- 230 Im, W. B., Binder, J. A., Dillon, G. H., Pregenzer, J. F., Im, H. K., and Altman, R. A. (1995). Acceleration of GABA-dependent desensitization by mutating threonine 266 to alanine of the alpha 6 subunit of rat GABAA receptors. Neurosci. Lett. 186, 203–207.
- 231 Chang, Y., Wang, R., Barot, S., and Weiss, D. S. (1996). Stoichiometry of a recombinant GABAA receptor. J. Neurosci. 16, 5415–5424.
- 232 Farrar, S. J., Whiting, P. J., Bonnert, T. P., and McKernan, R. M. (1999). Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer. J. Biol. Chem. 274, 10100–10104.
- 233 Baumann, S. W., Baur, R., and Sigel, E. (2001). Subunit arrangement of gamma-aminobutyric acid type A receptors. J. Biol. Chem. 276, 36275–36280.
- 234 Baumann, S. W., Baur, R., and Sigel, E. (2002). Forced subunit assembly in α1β2γ2 GABAA receptors. Insight into the absolute arrangement. J. Biol. Chem. 277, 46020–46025.
- 235 Burt, D. R., and Kamatchi, G. L. (1991). GABAA receptor subtypes: From pharmacology to molecular biology. FASEB J. 5, 2916–2923.
- 236 Wang, T. L., Guggino, W. B., and Cutting, G. R. (1994). A novel γ-aminobutyric acid receptor subunit (rho2) cloned from human retina forms bicuculline-insensitive homooligomeric receptors in Xenopus oocytes. J. Neurosci. 14, 6524–6531.
- 237 Shingai, R., Yanagi, K., Fukushima, T., Sakata, K., and Ogurusu, T. (1996). Functional expression of rat GABA receptor ρ3 subunit. Neurosci. Res. 26, 387–390.
- 238 Connolly, C. N., Wooltorton, J. R., Smart, T. G., and Moss, S. J. (1996). Subcellular localization of gamma-aminobutyric acid type A receptors is determined by receptor beta subunits. Proc. Nat. Acad. Sci. USA 93, 9899–9904.
- 239 Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G., and Moss, S. J. (1996). Assembly and cell surface expression of heteromeric and homomeric gamma-aminobutyric acid type A receptors. J. Biol. Chem. 271, 89–96.
- 240 Krishek, B. J., Moss, S. J., and Smart, T. G. (1996). Homomeric β1 γ-aminobutyric acid A receptor-ion channels: Evaluation of pharmacological and physiological properties. Mol. Pharmacol. 49, 494–504.
- 241 Wooltorton, J. R., Moss, S. J., and Smart, T. G. (1997b). Pharmacological and physiological characterization of murine homomeric β3 GABAA receptors. Eur. J. Neurosci. 9, 2225–2235.
- 242 Martinez-Torres, A., and Miledi, R. (2004). Expression of functional receptors by the human gamma-aminobutyric acid A γ2 subunit. Proc. Nat. Acad. Sci. USA 101, 3220–3223.
- 243 Sigel, E., Baur, R., Malherbe, P., and Mohler, H. (1989). The rat β1 subunit of the GABAA receptor forms a picrotoxin-sensitive anion channel open in the absence of GABA. FEBS Lett. 257, 377–379.
- 244 Pritchett, D. B., Sontheimer, H., Gorman, C. M., Kettenmann, H., Seeburg, P. H., and Schofield, P. R. (1988). Transient expression shows ligand gating and allosteric potentiation of GABAA receptor subunits. Science 242, 1306–1308.
- 245 Sanna, E., Garau, F., and Harris, R. A. (1995). Novel properties of homomeric β1 γ-aminobutyric acid type A receptors: Actions of the anesthetics propofol and pentobarbital. Mol. Pharmacol. 47, 213–217.
- 246 Verdoorn, T. A., Draguhn, A., Ymer, S., Seeburg, P. H., and Sakmann, B. (1990). Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron 4, 919–928.
- 247 Sigel, E., Baur, R., Trube, G., Mohler, H., and Malherbe, P. (1990). The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron 5, 703–711.
- 248 Knoflach, F., Rhyner, T., Villa, M., Kellenberger, S., Drescher, U., Malherbe, P., Sigel, E., and Mohler, H. (1992). The γ3 subunit of the GABAA-receptor confers sensitivity to benzodiazepine receptor ligands. FEBS Lett. 293, 191–194.
- 249 Angelotti, T. P., and Macdonald, R. L. (1993). Assembly of GABAA receptor subunits: α1β1 and α1β1γ2S subunits produce unique ion channels with dissimilar single-channel properties. J. Neurosci. 13, 1429–1440.
- 250 Taylor, P. M., Thomas, P., Gorrie, G. H., Connolly, C. N., Smart, T. G., and Moss, S. J. (1999). Identification of amino acid residues within GABAA receptor beta subunits that mediate both homomeric and heteromeric receptor expression. J. Neurosci. 19, 6360–6371.
- 251 Hamon, A., Morel, A., Hue, B., Verleye, M., and Gillardin, J. M. (2003). The modulatory effects of the anxiolytic etifoxine on GABAA receptors are mediated by the beta subunit. Neuropharmacology 45, 293–303.
- 252 Whiting, P. J., McAllister, G., Vassilatis, D., Bonnert, T. P., Heavens, R. P., Smith, D. W., Hewson, L., O'Donnell, R., Rigby, M. R., Sirinathsinghji, D. J., Marshall, G., Thompson, S. A., and Wafford, K. A. (1997). Neuronally restricted RNA splicing regulates the expression of a novel GABAA receptor subunit conferring atypical functional properties. J. Neurosci. 17, 5027–5037.
- 253 Enz, R., and Cutting, G. R. (1998). Molecular composition of GABAC receptors. Vision Res. 38, 1431–1441.
- 254 Pan, Z. H., Zhang, X., Zhang, Z., and Lipton, S. A. (1997). Evidence for co-assembly of GABA ρ1 with GABAA or glycine subunits in vitro. Soc. Neurosci. Abstr. 7, 6.
- 255 Pan, Z. H., Zhang, D., Zhang, X., and Lipton, S. A. (2000). Evidence for coassembly of mutant GABAC rho1 with GABAA γ2S, glycine α1 and glycine α2 receptor subunits in vitro. Eur. J. Neurosci. 12, 3137–3145.
- 256 Qian, H., and Ripps, H. (1999). Response kinetics and pharmacological properties of heteromeric receptors formed by co-assembly of GABA ρ and γ2 subunits. Proc. Roy. Soc. Lond. Ser. B: Biol. Sci. 266, 2419–2425.
- 257 Sieghart, W. (1995). Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol. Rev. 47, 181–234.
- 258 Verdoorn, T. A. (1994). Formation of heteromeric γ-aminobutyric acid type A receptors containing two different α subunits. Mol. Pharmacol. 45, 475–480.
- 259 Polenzani, L., Woodward, R. M., and Miledi, R. (1991). Expression of mammalian γ-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes. Proc. Nat. Acad. Sci. USA 88, 4318–4322.
- 260 Faure-Halley, C., Graham, D., Arbilla, S., and Langer, S. Z. (1993). Expression and properties of recombinant α1β2γ2 and α5β2γ2 forms of the rat GABAA receptor. Eur. J. Pharmacol. 246, 283–287.
- 261 Sigel, E., and Baur, R. (2000). Electrophysiological evidence for the coexistence of α1 and α6 subunits in a single functional GABAA receptor. J. Neurochem. 74, 2590–2596.
- 262 Hansen, S. L., Ebert, B., Fjalland, B., and Kristiansen, U. (2001). Effects of GABAA receptor partial agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different receptor subunit compositions. Br. J. Pharmacol. 133, 539–549.
- 263 Fisher, J. L., and Macdonald, R. L. (1997). Functional properties of recombinant GABAA receptors composed of single or multiple beta subunit subtypes. Neuropharmacology 36, 1601–1610.
- 264 Minier, F., and Sigel, E. (2004). Positioning of the alpha-subunit isoforms confers a functional signature to gamma-aminobutyric acid type A receptors. Proc. Nat. Acad. Sci. USA 101, 7769–7774.
- 265 Hevers, W., Korpi, E. R., and Luddens, H. (2000). Assembly of functional α6β3γ2δ GABAA receptors in vitro. Neuroreport 11, 4103–4106.
- 266 Neelands, T. R., and Macdonald, R. L. (1999). Incorporation of the pi subunit into functional gamma-aminobutyric acidA receptors. Mol. Pharmacol. 56, 598–610.
- 267 Baumann, S. W., Baur, R., and Sigel, E. (2003). Individual properties of the two functional agonist sites in GABAA receptors. J. Neurosci. 23, 11158–11166.
- 268 Kittler, J. T., Wang, J., Connolly, C. N., Vicini, S., Smart, T. G., and Moss, S. J. (2000). Analysis of GABAA receptor assembly in mammalian cell lines and hippocampal neurons using γ2 subunit green fluorescent protein chimeras. Mol. Cell. Neurosc. 16, 440–452.
- 269 Kittler, J. T., and Moss, S. J. (2003). Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: Implications for the efficacy of synaptic inhibition. Curr. Opin. Neurobiol. 13, 341–347.
- 270 Kittler, J. T., McAinsh, K., and Moss, S. J. (2002). Mechanisms of GABAA receptor assembly and trafficking: Implications for the modulation of inhibitory neurotransmission. Mol. Neurobiol. 26, 251–268.
- 271 Moss, S. J., and Smart, T. G. (2001). Constructing inhibitory synapses. Nat. Rev. Neurosci. 2, 240–250.
- 272 Twyman, R. E., and Macdonald, R. L. (1992). Neurosteroid regulation of GABAA receptor single-channel kinetic properties of mouse spinal cord neurons in culture. J. Physiol. 456, 215–245.
- 273 Wohlfarth, K. M., Bianchi, M. T., and Macdonald, R. L. (2002). Enhanced neurosteroid potentiation of ternary GABAA receptors containing the delta subunit. J. Neurosci. 22, 1541–1549.
- 274 Akk, G., and Steinbach, J. H. (2003). Low doses of ethanol and a neuroactive steroid positively interact to modulate rat GABAA receptor function. J. Physiol. 546, 641–646.
- 275 Bianchi, M. T., and Macdonald, R. L. (2003). Neurosteroids shift partial agonist activation of GABAA receptor channels from low- to high-efficacy gating patterns. J. Neurosci. 23, 10934–10943.
- 276 Angelotti, T. P., Uhler, M. D., and Macdonald, R. L. (1993). Enhancement of recombinant gamma-aminobutyric acid type A receptor currents by chronic activation of cAMP-dependent protein kinase. Mol. Pharmacol. 44, 1202–1210.
- 277 Corringer, P. J., Le Novere, N., and Changeux, J. P. (2000). Nicotinic receptors at the amino acid level. Annu. Rev. Pharmacol. Toxicol. 40, 431–458.
- 278 Le Novere, N., Corringer, P. J., and Changeux, J. P. (2002). The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences. J. Neurobiol. 53, 447–456.
- 279 Brejc, K., van Dijk, W. J., Klaassen, R. V., Schuurmans, M., van Dar Oost, J., Smit, A. B., and Sixma, T. K. (2001). Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276.
- 280 Taylor, P. M., Connolly, C. N., Kittler, J. T., Gorrie, G. H., Hosie, A., Smart, T. G., and Moss, S. J. (2000). Identification of residues within GABAA receptor alpha subunits that mediate specific assembly with receptor beta subunits. J. Neurosci. 20, 1297–1306.
- 281 Sarto, I., Wabnegger, L., Dogl, E., and Sieghart, W. (2002). Homologous sites of GABAA receptor α1, β3 and γ2 subunits are important for assembly. Neuropharmacology 43, 482–491.
- 282 Klausberger, T., Fuchs, K., Mayer, B., Ehya, N., and Sieghart, W. (2000). GABAA receptor assembly. Identification and structure of γ2 sequences forming the intersubunit contacts with α1 and β3 subunits. J. Biol. Chem. 275, 8921–8928.
- 283 Klausberger, T., Ehya, N., Fuchs, K., Fuchs, T., Ebert, V., Sarto, I., and Sieghart, W. (2001). Detection and binding properties of GABAA receptor assembly intermediates. J. Biol. Chem. 276, 16024–16032.
- 284 Bollan, K., Robertson, L. A., Tang, H., and Connolly, C. N. (2003). Multiple assembly signals in gamma-aminobutyric acid (type A) receptor subunits combine to drive receptor construction and composition. Biochem. Soc. Trans. 31, 875–879.
- 285 Bollan, K., King, D., Robertson, L. A., Brown, K., Taylor, P. M., Moss, S. J., and Connolly, C. N. (2003). GABAA receptor composition is determined by distinct assembly signals within alpha and beta subunits. J. Biol. Chem. 278, 4747–4755.
- 286 Srinivasan, S., Nichols, C. J., Lawless, G. M., Olsen, R. W., and Tobin, A. J. (1999). Two invariant tryptophans on the alpha1 subunit define domains necessary for GABAA receptor assembly. J. Biol. Chem. 274, 26633–26638.
- 287 Ehya, N., Sarto, I., Wabnegger, L., and Sieghart, W. (2003). Identification of an amino acid sequence within GABAA receptor β3 subunits that is important for receptor assembly. J. Neurochem. 84, 127–135.
- 288 Sarto, I., Klausberger, T., Ehya, N., Mayer, B., Fuchs, K., and Sieghart, W. (2002). A novel site on γ3 subunits important for assembly of GABAA receptors. J. Biol. Chem. 277, 30656–30664.
- 289 Teissere, J. A., and Czajkowski, C. (2001). β-Strand in the γ2 subunit lines the benzodiazepine binding site of the GABAA receptor: Structural rearrangements detected during channel gating. J. Neurosci. 21, 4977–4986.
- 290 Boileau, A. J., and Czajkowski, C. (1999). Identification of transduction elements for benzodiazepine modulation of the GABAA receptor: Three residues are required for allosteric coupling. J. Neurosci. 19, 10213–10220.
- 291 Buhr, A., Baur, R., and Sigel, E. (1997). Subtle changes in residue 77 of the gamma subunit of α1β2γ2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site. J. Biol. Chem. 272, 11799–11804.
- 292 Buhr, A., Schaerer, M. T., Baur, R., and Sigel, E. (1997). Residues at positions 206 and 209 of the alpha1 subunit of gamma-aminobutyric acidA receptors influence affinities for benzodiazepine binding site ligands. Mol. Pharmacol. 52, 676–682.
- 293 Buhr, A., and Sigel, E. (1997). A point mutation in the γ2 subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity. Proc. Nat. Acad. Sci. USA 94, 8824–8829.
- 294 Boileau, A. J., Evers, A. R., Davis, A. F., and Czajkowski, C. (1999). Mapping the agonist binding site of the GABAA receptor: Evidence for a beta-strand. J. Neurosci. 19, 4847–4854.
- 295 Sigel, E. (2002). Mapping of the benzodiazepine recognition site on GABAA receptors. Curr. Top. Med. Chem. 2, 833–839.
- 296 Fritschy, J. M., Johnson, D. K., Mohler, H., and Rudolph, U. (1998). Independent assembly and subcellular targeting of GABAA-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249, 99–102.
- 297
Sassoe-Pognetto, M.,
Panzanelli, P.,
Sieghart, W., and
Fritschy, J. M.
(2000).
Colocalization of multiple GABAA receptor subtypes with gephyrin at postsynaptic sites.
J. Comp. Neurol.
420,
481–498.
10.1002/(SICI)1096-9861(20000515)420:4<481::AID-CNE6>3.0.CO;2-5 CAS PubMed Web of Science® Google Scholar
- 298 Balasubramanian, S., Teissere, J. A., Raju, D. V., and Hall, R. A. (2004). Hetero-oligomerization between GABAA and GABAB receptors regulates GABAB receptor trafficking. J. Biol. Chem. 279, 18840–18850.
- 299 Liu, F., Wan, Q., Pristupa, Z. B., Yu, X. M., Wang, Y. T., and Niznik, H. B. (2000). Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors. Nature 403, 274–280.
- 300 Sokolova, E., Nistri, A., and Giniatullin, R. (2001). Negative cross talk between anionic GABAA and cationic P2X ionotropic receptors of rat dorsal root ganglion neurons. J. Neurosci. 21, 4958–4968.
- 301 Boue-Grabot, E., Toulme, E., Emerit, M. B., and Garret, M. (2004). Subunit-specific coupling between gamma-aminobutyric acid type A and P2X2 receptor channels. J. Biol. Chem. 279, 52517–52525.
- 302 Boue-Grabot, E., Emerit, M. B., Toulme, E., Seguela, P., and Garret, M. (2004). Cross-talk and co-trafficking between rho1/GABA receptors and ATP-gated channels. J. Biol. Chem. 279, 6967–6975.
- 303 Kneussel, M., Brandstatter, J. H., Laube, B., Stahl, S., Muller, U., Betz, H. (1999). Loss of postsynaptic GABAA receptor clustering in gephyrin deficient mice. J. Neurosci. 19, 9289–9297.
- 304 Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M., and Luscher, B. (1998). Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin. Nat. Neurosci. 1, 563–571.
- 305 Schweizer, C., Balsiger, S., Bluethmann, H., Mansuy, I. M., Fritschy, J. M., Mohler, H., and Luscher, B. (2003). The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses. Mol. Cell. Neurosci. 24, 442–450.
- 306 Kneussel, M., Brandstatter, J. H., Gasnier, B., Feng, G., Sanes, J. R., and Betz, H. (2001). Gephyrin-independent clustering of postsynaptic GABAA receptor subtypes. Mol. Cell. Neurosci. 17, 973–982.
- 307 Beck, M., Brickley, K., Wilkinson, H. L., Sharma, S., Smith, M., Chazot, P. L., Pollard, S., and Stephenson, F. A. (2002). Identification, molecular cloning, and characterization of a novel GABAA receptor-associated protein, GRIF-1. J. Biol. Chem. 277, 30079–30090.
- 308 Bedford, F. K., Kittler, J. T., Muller, E., Thomas, P., Uren, J. M., Merlo, D., Wisden, W., Triller, A., Smart, T. G., and Moss, S. J. (2001). GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1. Nat. Neurosci. 4, 908–916.
- 309 Wang, H., Bedford, F. K., Brandon, N. J., Moss, S. J., and Olsen, R. W. (1999). GABAA receptor associated protein links GABAA receptors and the cytoskeleton. Nature 397, 69–72.
- 310 Nymann-Andersen, J., Wang, H., Chen, L., Kittler, J. T., Moss, S. J., and Olsen, R. W. (2002). Subunit specificity and interaction domain between GABAA receptor- associated protein (GABARAP) and GABAA receptors. J. Neurochem. 80, 815–823.
- 311 Sagiv, Y., Legesse-Miller, A., Porat, A., and Elazar, Z. (2000). GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28. EMBO J. 19, 1494–1504.
- 312 Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., and Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728.
- 313 Ohsumi, Y. (2001). Molecular dissection of autophagy: Two ubiquitinlike systems. Nat. Rev. Mol. Cell Biol. 2, 211–216.
- 314 Coyle, J. E., Qamar, S., Rajashankar, K. R., and Nikolov, D. B. (2002). Structure of GABARAP in two conformations: Implications for GABAA receptor localization and tubulin binding. Neuron 33, 63–74.
- 315 Chen, L., Wang, H., Vicini, S., and Olsen, R. W. (2000). The gamma-aminobutyric acid type A receptor-associated protein promotes GABAA receptor clustering and modulates the channel kinetics. Proc. Nat. Acad. Sci. USA 97, 11557–11562.
- 316 Kittler, J. T., Rostaing, P., Schiavo, G., Fritschy, J. M., Olsen, R., Triller, A., and Moss, S. J. (2001). The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABAA receptors. Mol. Cell. Neurosci. 18, 13–25.
- 317 Leil, T. A., Chen, Z. W., Chang, C. S. S., and Olsen, R. W. (2004). GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons. J. Neurosci. 24, 11429–11438.
- 318 Kanematsu, T., Jang, I. S., Yamaguchi, T., Nagahama, H., Yoshimura, K., Hidaka, K., Matsuda, M., Takeuchi, H., Misumi, Y., Nakayama, K., Yamamoto, T., Akaike, N., Hirata, M., and Nakayama, K. (2002). Role of the PLC-related, catalytically inactive protein p130 in GABAA receptor function. EMBO J. 21, 1004–1011.
- 319 Nusser, Z., Cull-Candy, S., and Farrant, M. (1997). Differences in synaptic GABAA receptor number underlie variation in GABA mini amplitude. Neuron 19, 697–709.
- 320 Nusser, Z., Hajos, N., Somogyi, P., and Mody, I. (1998). Increased number of synaptic GABAA receptors underlies potentiation at hippocampal inhibitory synapses. Nature 395, 172–177.
- 321 Wan, Q., Xiong, Z. G., Man, H. Y., Ackerley, C. A., Braunton, J., Lu, W. Y., Becker, L. E., MacDonald, J. F., and Wang, Y. T. (1997). Recruitment of functional GABAA receptors to postsynaptic domains by insulin. Nature 388, 686–690.
- 322 Brunig, I., Penschuck, S., Berninger, B., Benson, J., and Fritschy, J. M. (2001). BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABAA receptor surface expression. Eur. J. Neurosci. 13, 1320–1328.
- 323 el-Husseini, Ael-D., and Bredt, D. S. (2002). Protein palmitoylation: A regulator of neuronal development and function. Nat. Rev. Neurosci. 3, 791–802.
- 324 Bijlmakers, M. J., and Marsh, M. (2003). The on-off story of protein palmitoylation. Trends Cell Biol. 13, 32–42.
- 325 Rathenberg, J., Kittler, J. T., and Moss, S. J. (2004). Palmitoylation regulates the clustering and cell surface stability of GABAA receptors. Mol. Cell. Neurosci. 26, 251–257.
- 326 Keller, C. A., Yuan, X., Panzanelli, P., Martin, M. L., Alldred, M., Sassoe-Pognetto, M., and Luscher, B. (2004). The γ2 subunit of GABAA receptors is a substrate for palmitoylation by GODZ. J. Neurosci. 24, 5881–5891.
- 327 Tehrani, M. H., and Barnes, E. M., Jr. (1993). Identification of GABAA/benzodiazepine receptors on clathrin-coated vesicles from rat brain. J. Neurochem. 60, 1755–1761.
- 328 Tehrani, M. H., Baumgartner, B. J., and Barnes, E. M., Jr. (1997). Clathrin-coated vesicles from bovine brain contain uncoupled GABAA receptors. Brain Res. 776, 195–203.
- 329 Barnes, E. M., Jr. (2001). Assembly and intracellular trafficking of GABAA receptors. Int. Rev. Neurobiol. 48, 1–29.
- 330 Kittler, J. T., Delmas, P., Jovanovic, J. N., Brown, D. A., Smart, T. G., and Moss, S. J. (2000). Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J. Neurosci. 20, 7972–7977.
- 331 Herring, D., Huang, R., Singh, M., Robinson, L. C., Dillon, G. H., and Leidenheimer, N. J. (2003). Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a dileucine AP2 adaptin-binding motif within the β2 subunit of the receptor. J. Biol. Chem. 278, 24046–24052.
- 332 Brandon, N., Jovanovic, J., and Moss, S. (2002). Multiple roles of protein kinases in the modulation of gamma-aminobutyric acidA receptor function and cell surface expression. Pharmacol. Ther. 94, 113–122.
- 333 Wang, X., Zhong, P., and Yan, Z. (2002). Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J. Neurosci. 22, 9185–9193.
- 334 Huidobro-Toro, J. P., Valenzuela, C. F., and Harris, R. A. (1996). Modulation of GABAA receptor function by G-protein coupled 5-HT2C receptor. Neuropharmacology 35, 1355–1363.
- 335 Feng, J., Cai, X., Zhao, J., and Yan, Z. (2001). Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J. Neurosci. 21, 6502–6511.
- 336 Cai, X., Flores-Hernandez, J., Feng, J., and Yan, Z. (2002). Activity-dependent bidirectional regulation of GABAA receptor channels by the 5-HT4 receptor-mediated signalling in rat prefrontal cortical pyramidal neurons. J. Physiol. 540, 743–759.
- 337 Browning, M. D., Bureau, M., Dudek, E. M., Olsen, R. W. (1990). Protein kinase C and cAMP-dependent protein kinase phosphorylate the β subunit of the purified γ-aminobutyric acid A receptor. Proc. Nat. Acad. Sci. USA 87, 1315–1318.
- 338 Cheun, J. E., and Yeh, H. H. (1993). Modulation of GABAA receptor-activated current by norepinephrine in cerebellar Purkinje cells. Neuroscience 51, 951–960.
- 339 Moss, S. J., Doherty, C. A., and Huganir, R. L. (1992). Identification of the protein kinase A and protein kinase C phosphorylation sites within the intracellular domains of the β1, γ2S and γ2L GABAA receptor subunits. J. Biol. Chem. 267, 14470–14476.
- 340 Moss, S. J., Smart, T. G., Blackstone, C. D., and Huganir, R. L. (1992). Functional modulation of GABAA receptors by cAMP-dependent protein phosphorylation. Science 257, 661–665.
- 341 Feigenspan, A., and Bormann, J. (1994). Facilitation of GABAergic signaling in the retina by receptors stimulating adenylate cyclase. Proc. Nat. Acad. Sci. USA 91, 10893–10897.
- 342 Cheun, J. E., and Yeh, H. H. (1996). Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: Cyclic AMP as intracellular intermediary. Neuroscience 74, 835–844.
- 343 Kapur, J., and Macdonald, R. L. (1996). Cyclic AMP-dependent protein kinase enhances hippocampal dentate granule cell GABAA receptor currents. J. Neurophysiol. 76, 2626–2634.
- 344 Jones, M. V., and Westbrook, G. L. (1997). Shaping of IPSCs by endogenous calcineurin activity. J. Neurosci. 17, 7626–7633.
- 345 Poisbeau, P., Cheney, M. C., Browning, M. D., and Mody, I. (1999). Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J. Neurosci. 19, 674–683.
- 346 Kellenberger, S., Malherbe, P., and Sigel, E. (1992). Function of the α1β2γ2S gamma-aminobutyric acid type A receptor is modulated by protein kinase C via multiple phosphorylation sites. J. Biol. Chem. 267, 25660–25663.
- 347 Krishek, B. J., Xie, X., Blackstone, C. D., Huganir, R. L., Moss, S. J., and Smart, T. G. (1994). Regulation of GABAA receptor function by protein kinase C phosphorylation. Neuron 12, 1081–1095.
- 348 Lin, Y. F., Angelotti, T. P., Dudek, E. M., Browning, M. D., and Macdonald, R. L. (1996). Enhancement of recombinant α1β1γ2L γ-aminobutyric acid A receptor whole-cell currents by protein kinase C is mediated through phosphorylation of both β1 and γ2L subunits. Mol. Pharmacol. 50, 185–195.
- 349 Brandon, N. J., Delmas, P., Kittler, J. T., McDonald, B. J., Sieghart, W., Brown, D. A., Smart, T. G., and Moss, S. J. (2000). GABAA receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway. J. Biol. Chem. 275, 38856–38862.
- 350 Hinkle, D. J., and Macdonald, R. L. (2003). Beta subunit phosphorylation selectively increases fast desensitization and prolongs deactivation of α1β1γ2L and α1β3γ2L GABAA receptor currents. J. Neurosci. 23, 11698–11710.
- 351 Valenzuela, C. F., Machu, T. K., McKernan, R. M., Whiting, P., VanRenterghem, B. B., McManaman, J. L., Brozowski, S. J., Smith, G. B., Olsen, R. W., and Harris, R. A. (1995). Tyrosine kinase phosphorylation of GABAA receptors. Mol. Brain Res. 1/2, 165–172.
- 352 Moss, S. J., Gorrie, G., Amato, A., and Smart, T. G. (1995). Modulation of GABAA receptors by tyrosine phosphorylation. Nature 377, 344–348.
- 353 Mizoguchi, Y., Ishibashi, H., and Nabekura, J. (2003). The action of BDNF on GABAA currents changes from potentiating to suppressing during maturation of rat hippocampal CA1 pyramidal neurons. J. Physiol. 548, 703–709.
- 354 Jovanovic, J. N., Thomas, P., Kittler, J. T., Smart, T. G., and Moss, S. J. (2004). Brain-derived neurotrophic factor modulates fast synaptic inhibition by regulating GABAA receptor phosphorylation, activity, and cell-surface stability. J. Neurosci. 24, 522–530.
- 355 Palma, E., Torchia, G., Limatola, C., Trettel, F., Arcella, A., Cantore, G., Di Gennaro, G., Manfredi, M., Esposito, V., Quarato, P. P., Miledi, R., and Eusebi, F. (2005). BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes. Proc. Nat. Acad. Sci. USA 102, 1667–1672.
- 356 McDonald, B. J., and Moss, S. J. (1994). Differential phosphorylation of intracellular domains of γ-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. J. Biol. Chem. 269, 18111–18117.
- 357 McDonald, B. J., and Moss, S. J. (1997). Conserved phosphorylation of the intracellular domains of GABAA receptor β2 and β3 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. Neuropharmacology 36, 1377–1385.
- 358 McDonald, B. J., Amato, A., Connolly, C. N., Benke, D., Moss, S. J., and Smart, T. G. (1998). Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase. Nat. Neurosci. 1, 23–28.
- 359 Brandon, N. J., Uren, J. M., Kittler, J. T., Wang, H., Olsen, R., Parker, P. J., and Moss, S. J. (1999). Subunit-specific association of protein kinase C and the receptor for activated C kinase with GABA type-A receptors. J. Neurosci. 19, 9228–9234.
- 360 Brandon, N. J., Jovanovic, J. N., Smart, T. G., and Moss, S. J. (2002). Receptor for activated C kinase-1 facilitates protein kinase C-dependent phosphorylation and functional modulation of GABAA receptors with the activation of G-protein-coupled receptors. J. Neurosci. 22, 6353–6361.
- 361 Brandon, N. J., Delmas, P., Hill, J., Smart, T. G., and Moss, S. J. (2001). Constitutive tyrosine phosphorylation of the GABAA receptor γ2 subunit in rat brain. Neuropharmacology 41, 745–752.
- 362 Moss, S. J., and Smart, T. G. (1996). Modulation of amino acid-gated ion channels by protein phosphorylation. Int. Rev. Neurobiol. 39, 1–52.
- 363 Connolly, C. N., Kittler, J. T., Thomas, P., Uren, J. M., Brandon, N. J., Smart, T. G., and Moss, S. J. (1999). Cell surface stability of gammaaminobutyric acid type A receptors. Dependence on protein kinase C activity and subunit composition. J. Biol. Chem. 274, 36565–36572.
- 364 Feng, J., Cai, X., Zhao, J., and Yan, Z. (2001). Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J. Neurosci. 21, 6502–6511.
- 365 Michel, J. J., and Scott, J. D. (2002). AKAP mediated signal transduction. Annu. Rev. in Pharmacol. Toxicol. 42, 235–257.
- 366 Brandon, N. J., Jovanovic, J., Colledge, M., Kittler, J. T., Brandon, J. M., Scott, J. D., and Moss, S. J. (2003). A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABAA receptors by cAMP-dependent protein kinase via selective interaction with receptor β subunits. Mol. Cell. Neurosci. 22, 87–97.
- 367 Lin, J. W., Wyszynski, M., Madhavan, R., Sealock, R., Kim, J. U., and Sheng, M. (1998). Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18, 2017–2027.
- 368 Rudolph, U., Crestani, F., and Mohler, H. (2001). GABAA receptor subtypes: Dissecting their pharmacological functions. Trends Pharmacol. Sci. 22, 188–194.
- 369 Rudolph, U., and Mohler, H. (2004). Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 44, 475–498.
- 370 Reynolds, D. S., Rosahl, T. W., Cirone, J., O'Meara, G. F., Haythornthwaite, A., Newman, R. J., Myers, J., Sur, C., Howell, O., Rutter, A. R., Atack, J., Macaulay, A. J., Hadingham, K. L., Hutson, P. H., Belelli, D., Lambert, J. J., Dawson, G. R., McKernan, R., Whiting, P. J., and Wafford, K. A. (2003). Sedation and anesthesia mediated by distinct GABAA receptor isoforms. J. Neurosci. 23, 8608–8617.
- 371 Jurd, R., Arras, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., Zaugg, M., Vogt, K. E., Ledermann, B., Antkowiak, B., and Rudolph, U. (2003). General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit. FASEB J. 17, 250–252.
- 372 Farb, D. H., Borden, L. A., Chan, C. Y., Czajkowski, C. M., Gibbs, T. T., and Schiller, G. D. (1984). Modulation of neuronal function through benzodiazepine receptors: Biochemical and electrophysiological studies of neurons in primary monolayer cell culture. Annu. Proc. NY Acad. Sci. 435, 1–31.
- 373 Chan, C. Y., Gibbs, T. T., Borden, L. A., and Farb, D. H. (1983). Multiple embryonic benzodiazepine binding sites: Evidence for functionality. Life Sci. 33, 2061–2069.
- 374 Chan, C. Y., and Farb, D. H. (1985). Modulation of neurotransmitter action: Control of the gamma-aminobutyric acid response through the benzodiazepine receptor. J. Neurosci. 5, 2365–2373.
- 375 Platt, D. M., RowLetters, J. K., Spealman, R. D., Cook, J., and Ma, C. (2002). Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys. Psychopharmacology 164, 151–159.
- 376 Kralic, J. E., Korpi, E. R., O'Buckley, T. K., Homanics, G. E., and Morrow, A. L. (2002). Molecular and pharmacological characterization of GABAA receptor alpha1 subunit knockout mice. J. Pharmacol. Exp. Ther. 302, 1037–1045.
- 377 Kralic, J. E., O'Buckley, T. K., Khisti, R. T., Hodge, C. W., Homanics, G. E., and Morrow, A. L. (2002). GABAA receptor alpha1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43, 685–694.
- 378 Goldstein, P. A., Elsen, F. P., Ying, S. W., Ferguson, C., Homanics, G. E., and Harrison, N. L. (2002). Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABAA receptor alpha1 subunit. J. Neurophysiol. 88, 3208–3217.
- 379 Vicini, S., Losi, G., and Homanics, G. E. (2002). GABAA receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 43, 646–650.
- 380 Kralic, J. E., Wheeler, M., Renzi, K., Ferguson, C., O'Buckley, T. K., Grobin, A. C., Morrow, A. L., and Homanics, G. E. (2003). Deletion of GABAA receptor α1 subunit-containing receptors alters responses to ethanol and other anesthetics. J. Pharmacol. Exp. Ther. 305, 600–607.
- 381 Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J. A., Fritschy, J. M., Martin, J. R., Bluethmann, H., and Mohler, H. (1999). Benzodiazepine actions mediated by specific gamma-aminobutyric acidA receptor subtypes. Nature 401, 796–800. Erratum 404, 629 2000..
- 382 Crestani, F., Martin, J. R., Mohler, H., and Rudolph, U. (2000). Mechanism of action of the hypnotic zolpidem in vivo. Br. J. Pharmacol. 131, 1251–1256.
- 383 Crestani, F., Martin, J. R., Mohler, H., and Rudolph, U. (2000). Resolving differences in GABAA receptor mutant mouse studies. Nat. Neurosci. 3, 1059.
- 384 Low, K., Crestani, F., Keist, R., Benke, D., Brunig, I., Benson, J. A., Fritschy, J. M., Rulicke, T., Bluethmann, H., Mohler, H., and Rudolph, U. (2000). Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134.
- 385 McKernan, R. M., Rosahl, T. W., Reynolds, D. S., Sur, C., Wafford, K. A., Atack, J. R., Farrar, S., Myers, J., Cook, G., Ferris, P., Garrett, L., Bristow, L., Marshall, G., Macaulay, A., Brown, N., Howell, O., Moore, K. W., Carling, R. W., Street, L. J., Castro, J. L., Ragan, C. I., Dawson, G. R., and Whiting, P. J. (2000). Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat. Neurosci. 3, 587–592.
- 386 Lippa, A., Czobor, P., Stark, J., Beer, B., Kostakis, E., Gravielle, M., Bandyopadhyay, S., Russek, S. J., Gibbs, T. T., Farb, D. H., and Skolnick, P. (2005). Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator. Proc. Nat. Acad. Sci. USA 102, 7380–7385.
- 387 Collins, I., Moyes, C., Davey, W. B., Rowley, M., and Bromidge, F. A. (2002). 3-Heteroaryl-2-pyridones: Benzodiazepine site ligands with functional delectivity for alpha2/alpha3-subtypes of human GABAA receptor-ion channels. J. Med. Chem. 45, 1887–1900.
- 388 Crestani, F., Low, K., Keist, R., Mandelli, M., Mohler, H., and Rudolph, U. (2001). Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. 59, 442–445.
- 389 Sohal, V. S., Keist, R., Rudolph, U., and Huguenard, J. R. (2003). Dynamic GABAA receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. J. Neurosci. 23, 3649–3657.
- 390 Smith, S. S., Gong, Q. H., Li, X., Moran, M. H., Bitran, D., Frye, C. A., and Hsu, F. C. (1998). Withdrawal from 3alpha-OH-5alpha-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety. J. Neurosci. 18, 5275–5284.
- 391 Gulinello, M., Gong, Q. H., Li, X., and Smith, S. S. (2001). Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 910, 55–66.
- 392 Gulinello, M., Gong, Q. H., and Smith, S. S. (2003). Progesterone withdrawal increases the anxiolytic actions of gaboxadol: Role of α4βδ GABAA receptors. Neuroreport 14, 43–46.
- 393 Gulinello, M., and Smith, S. S. (2003). Anxiogenic effects of neurosteroid exposure: Sex differences and altered GABAA receptor pharmacology in adult rats. J. Pharmacol. Exp. Ther. 305, 541–548.
- 394 Hsu, F. C., and Smith, S. S. (2003). Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: Dependence on GABAA receptor α4 subunit upregulation. J. Neurophysiol. 89, 186–198.
- 395 Navarro, J. F., Buron, E., and Martin-Lopez, M. (2002). Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the α5 subunit, in the elevated plus-maze test. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1389–1392.
- 396 Collinson, N., Kuenzi, F. M., Jarolimek, W., Maubach, K. A., Cothliff, R., Sur, C., Smith, A., Out, F. M., Howell, O., Atack, J. R., McKernan, R. M., Seabrook, G. R., Dawson, G. R., Whiting, P. J., and Rosahl, T. W. (2002). Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J. Neurosci. 22, 5572–5580.
- 397 Crestani, F., Keist, R., Fritschy, J. M., Benke, D., Vogt, K., Prut, L., Bluthmann, H., Mohler, H., and Rudolph, U. (2002). Trace fear conditioning involves hippocampal alpha5 GABAA receptors. Proc. Nat. Acad. Sci. USA 99, 8980–8985.
- 398 Homanics, G. E., Ferguson, C., Quinlan, J. J., Daggett, J., Snyder, K., Lagenaur, C., Mi, Z. P., Wang, X. H., Grayson, D. R., and Firestone, L. L. (1997). Gene knockout of the α6 subunit of the gamma-aminobutyric acid type A receptor: Lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol. 51, 588–596.
- 399 Korpi, E. R., Koikkalainen, P., Vekovischeva, O. Y., Makela, R., Kleinz, R., Uusi-Oukari, M., and Wisden, W. (1999). Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: Evidence from alpha 6-subunit-deficient mice. Eur. J. Neurosci. 11, 233–240.
- 400 Vekovischeva, O., Uusi-Oukari, M., and Korpi, E. R. (2003). Tolerance to diazepam-induced motor impairment: A study with GABAA receptor α6 subunit knockout mice. Neurochem. Res. 28, 757–764.
- 401 Brickley, S. G., Revilla, V., Cull-Candy, S. G., Wisden, W., and Farrant, M. (2001). Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409, 88–92.
- 402 Brooks-Kayal, A. R., Shumate, M. D., Jin, H., Rikhter, T. Y., and Coulter, D. A. (1998). Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy. Nat. Med. 4, 1166–1172. Erratum 5, 590 1999..
- 403 Loup, F., Wieser, H. G., Yonekawa, Y., Aguzzi, A., and Fritschy, J. M. (2000). Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J. Neurosci. 20, 5401–5419.
- 404 Pirker, S., Schwarzer, C., Czech, T., Baumgartner, C., Pockberger, H., Maier, H., Hauer, B., Sieghart, W., Furtinger, S., and Sperk, G. (2003). Increased expression of GABAA receptor beta-subunits in the hippocampus of patients with temporal lobe epilepsy. J. Neuropathol. Exp. Neurol. 62, 820–834.
- 405 Tsunashima, K., Schwarzer, C., Kirchmair, E., Sieghart, W., and Sperk, G. (1997). GABAA receptor subunits in the rat hippocampus III: Altered messenger RNA expression in kainic acid-induced epilepsy. Neuroscience 80, 1019–1032.
- 406 Schwarzer, C., Tsunashima, K., Wanzenbock, C., Fuchs, K., Sieghart, W., and Sperk, G. (1997). GABAA receptor subunits in the rat hippocampus II: Altered distribution in kainic acid-induced temporal lobe epilepsy. Neuroscience 80, 1001–1017.
- 407 Krasowski, M. D., Rick, C. E., Harrison, N. L., Firestone, L. L., and Homanics, G. E. (1998). A deficit of functional GABAA receptors in neurons of β3 subunit knockout mice. Neurosci. Lett. 240, 81–84.
- 408 Homanics, G. E., DeLorey, T. M., Firestone, L. L., Quinlan, J. J., Handforth, A., Harrison, N. L., Krasowski, M. D., Rick, C. E., Korpi, E. R., Makela, R., Brilliant, M. H., Hagiwara, N., Ferguson, C., Snyder, K., and Olsen, R. W. (1997). Mice devoid of gamma-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Nat. Acad. Sci. USA 94, 4143–4138.
- 409 Ugarte, S. D., Homanics, G. E., Firestone, L. L., and Hammond, D. L. (2000). Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the β3 subunit of the GABAA receptor. Neuroscience 95, 795–806.
- 410 DeLorey, T. M., Handforth, A., Anagnostaras, S. G., Homanics, G. E., Minassian, B. A., Asatourian, A., Fanselow, M. S., Delgado-Escueta, A., Ellison, G. D., and Olsen, R. W. (1998). Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci. 18, 8505–8514.
- 411 Huntsman, M. M., Porcello, D. M., Homanics, G. E., DeLorey, T. M., and Huguenard, J. R. (1999). Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283, 541–543.
- 412 Ramadan, E., Fu, Z., Losi, G., Homanics, G. E., Neale, J. H., and Vicini, S. (2003). GABAA receptor β3 subunit deletion decreases α2/3 subunits and IPSC duration. J. Neurophysiol. 89, 128–134.
- 413 Quinlan, J. J., Homanics, G. E., and Firestone, L. L. (1998). Anesthesia sensitivity in mice that lack the β3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology 88, 775–780.
- 414 Laposky, A. D., Homanics, G. E., Basile, A., and Mendelson, W. B. (2001). Deletion of the GABAA receptor β3 subunit eliminates the hypnotic actions of oleamide in mice. Neuroreport 12, 4143–4147.
- 415 Wong, S. M., Cheng, G., Homanics, G. E., and Kendig, J. J. (2001). Enflurane actions on spinal cords from mice that lack the β3 subunit of the GABAA receptor. Anesthesiology 95, 154–164.
- 416 Wisor, J. P., DeLorey, T. M., Homanics, G. E., and Edgar, D. M. (2002). Sleep states and sleep electroencephalographic spectral power in mice lacking the β3 subunit of the GABAA receptor. Brain Res. 955, 221–228.
- 417 Gunther, U., Benson, J., Benke, D., Fritschy, J. M., Reyes, G., Knoflach, F., Crestani, F., Aguzzi, A., Arigoni, M., Lang, Y., Bluethmann, H., Mohler, H., and Luscher, B. (1995). Benzodiazepine-insensitive mice generated by targeted disruption of the γ2 subunit gene of gamma-aminobutyric acid type A receptors. Proc. Nat. Acad. Sci. USA 92, 7749–7753.
- 418 Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J. M., Luscher, B., and Mohler, H. (1999). Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2, 833–839.
- 419 Quinlan, J. J., Firestone, L. L., and Homanics, G. E. (2000). Mice lacking the long splice variant of the γ2 subunit of the GABAA receptor are more sensitive to benzodiazepines. Pharmacol. Biochem. Behav. 66, 371–374.
- 420 Belelli, D., Casula, A., Ling, A., and Lambert, J. J. (2002). The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology 43, 651–661.
- 421 Spigelman, I., Li, Z., Banerjee, P. K., Mihalek, R. M., Homanics, G. E., and Olsen, R. W. (2002). Behavior and physiology of mice lacking the GABAA-receptor delta subunit. Epilepsia 43, 3–8.
- 422 Peng, Z., Hauer, B., Mihalek, R. M., Homanics, G. E., Sieghart, W., Olsen, R. W., and Houser, C. R. (2002). GABAA receptor changes in delta subunit-deficient mice: Altered expression of α4 and γ2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197.
- 423 Korpi, E. R., Mihalek, R. M., Sinkkonen, S. T., Hauer, B., Hevers, W., Homanics, G. E., Sieghart, W., and Luddens, H. (2002). Altered receptor subtypes in the forebrain of GABAA receptor delta subunit-deficient mice: Recruitment of γ2 subunits. Neuroscience 109, 733–743.
- 424 Mihalek, R. M., Banerjee, P. K., Korpi, E. R., Quinlan, J. J., Firestone, L. L., Mi, Z. P., Lagenaur, C., Tretter, V., Sieghart, W., Anagnostaras, S. G., Sage, J. R., Fanselow, M. S., Guidotti, A., Spigelman, I., Li, Z., DeLorey, T. M., Olsen, R. W., and Homanics, G. E. (1999). Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc. Nat. Acad. Sci. USA 96, 12905–12910.
- 425 Porcello, D. M., Huntsman, M. M., Mihalek, R. M., Homanics, G. E., and Huguenard, J. R. (2003). Intact fast synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking the δ subunit. J. Neurophysiol. 89, 1378–1386.
- 426 Mihalek, R. M., Bowers, B. J., Wehner, J. M., Kralic, J. E., VanDoren, M. J., Morrow, A. L., and Homanics, G. E. (2001). GABAA-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin. Exp. Res. 25, 1708–1718.
- 427 Davies, P. A., Hanna, M. C., Hales, T. G., and Kirkness, E. F. (1997). Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit. Nature 385, 820–823.
- 428 Macdonald, R. L., and Olsen, R. W. (1994). GABAA receptor channels. Annu. Rev. Neurosci. 17, 569–602.
- 429 Ueno, S., Bracamontes, J., Zorumski, C., Weiss, D. S., and Steinbach, J. H. (1997). Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J. Neurosci. 17, 625–634.
- 430 Wagner, D. A., and Czajkowski, C. (2001). Structure and dynamics of the GABA binding pocket: A narrowing cleft that constricts during activation. J. Neurosci. 21, 67–74.
- 431 Bianchi, M. T., and Macdonald, R. L. (2001). Agonist trapping by GABAA receptor channels. J. Neurosci. 21, 9083–9091.
- 432 Sigel, E., Baur, R., Kellenberger, S., and Malherbe, P. (1992). Point mutations affecting antagonist affinity and agonist dependent gating of GABAA receptor channels. EMBO J. 11, 2017–2023.
- 433 Amin, J., and Weiss, D. S. (1993). GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital. Nature 366, 565–569.
- 434 Schmieden, V., Kuhse, J., and Betz, H. (1993). Mutation of glycine receptor subunit creates β-alanine receptor responsive to GABA. Science 262, 256–258.
- 435 Horenstein, J., Wagner, D. A., Czajkowski, C., and Akabas, M. H. (2001). Protein mobility and GABA-induced conformational changes in GABAA receptor pore-lining M2 segment. Nat. Neurosci. 4, 477–485.
- 436 Bera, A. K., Chatav, M., and Akabas, M. H. (2002). GABAA receptor M2–M3 loop secondary structure and changes in accessibility during channel gating. J. Biol. Chem. 277, 43002–43010.
- 437 Koshland, D. E., Jr., Nemethy, G., and Filmer, D. (1966). Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5, 365–385.
- 438Fersht, A. (1985). Enzyme Structure and Mechanism (monograph). W. H. Freeman, New York, 1985, pp. 263–346.
- 439 Jones, M. V., Sahara, Y., Dzubay, J. A., and Westbrook, G. L. (1998). Defining affinity with the GABAA receptor. J. Neurosci. 18, 8590–8604.
- 440 Jones, M. V., Jonas, P., Sahara, Y., and Westbrook, G. L. (2001). Microscopic kinetics and energetics distinguish GABAA receptor agonists from antagonists. Biophys. J. 81, 2660–2670.
- 441 Chang, Y., and Weiss, D. S. (1999). Channel opening locks agonist onto the GABAC receptor. Nat. Neurosci. 2, 219–225.
- 442 Unwin, N. (1995). Acetylcholine receptor channel imaged in the open state. Nature 373, 37–43.
- 443 Miyazawa, A., Fujiyoshi, Y., and Unwin, N. (2003). Structure and gating mechanism of the acetylcholine receptor pore. Nature 424, 949–955.
- 444 Sine, S. M., and Steinbach, J. H. (1986). Activation of acetylcholine receptors on clonal mammalian BC3H-1 cells by low concentrations of agonist. J. Physiol. 373, 129–162.
- 445 Zhang, Y., Chen, J., and Auerbach, A. (1995). Activation of recombinant mouse acetylcholine receptors by acetylcholine, carbamylcholine and tetramethylammonium. J. Physiol. 486, 189–206.
- 446 Akk, G., and Auerbach, A. (1996). Inorganic, monovalent cations compete with agonists for the transmitter binding site of nicotinic acetylcholine receptors. Biophys. J. 70, 2652–2658.
- 447 Baur, R., and Sigel, E. (2003). On high- and low-affinity agonist sites in GABAA receptors. J. Neurochem. 87, 325–332.
- 448 Gingrich, K. J., Roberts, W. A., and Kass, R. S. (1995). Dependence of the GABA-A receptor gating kinetics on the alpha-subunit isoform: Implications for structure-function relations and synaptic transmission. J. Physiol. 489, 529–543.
- 449 Smith, G. B., and Olsen, R. W. (1994). Identification of a [3H]muscimol photoaffinity substrate in the bovine gamma-aminobutyric acidA receptor alpha subunit. J. Biol. Chem. 269, 20380–20387.
- 450 Westh-Hansen, S. E., Rasmussen, P. B., Hastrup, S., Nabekura, J., Noguchi, K., Akaike, N., Witt, M. R., and Nielsen, M. (1997). Decreased agonist sensitivity of human GABAA receptors by an amino acid variant, isoleucine to valine, in the α1 subunit. Eur. J. Pharmacol. 329, 253–257.
- 451 Westh-Hansen, S. E., Witt, M. R., Dekermendjian, K., Liljefors, T., Rasmussen, P. B., and Nielsen, M. (1999). Arginine residue 120 of the human GABAA receptor α1, subunit is essential for GABA binding and chloride ion current gating. Neuroreport 10, 2417–2421.
- 452 Hartvig, L., Lukensmejer, B., Liljefors, T., and Dekermendjian, K. (2000). Two conserved arginines in the extracellular N-terminal domain of the GABAA receptor α5 subunit are crucial for receptor function. J. Neurochem. 75, 1746–1753.
- 453 Newell, J. G., and Czajkowski, C. (2003). The GABAA receptor α1 subunit Pro174-Asp191 segment is involved in GABA binding and channel gating. J. Biol. Chem. 278, 13166–13172.
- 454 Boileau, A. J., Newell, J. G., and Czajkowski, C. (2002). GABAA receptor β2 Tyr97 and Leu99 line the GABA-binding site. Insights into mechanisms of agonist and antagonist actions. J. Biol. Chem. 277, 2931–2937.
- 455 Amin, J., Brooks-Kayal, A., and Weiss, D. S. (1997). Two tyrosine residues on the a subunit are crucial for benzodiazepine binding and allosteric modulation of γ-aminobutyric acidA receptors. Mol. Pharmacol. 51, 833–841.
- 456 Smit, A. B., Brejc, K., Syed, N., and Sixma, T. K. (2003). Structure and function of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Annu. Proc. NY Acad. Sci. 998, 81–92.
- 457 Cromer, B. A., Morton, C. J., and Parker, M. W. (2002). Anxiety over GABAA receptor structure relieved by AChBP. Trends Biochem. Sci. 27, 280–287.
- 458 Xiu, X., Hanek, A. P., Wang, J., Lester, H. A., and Dougherty, D. A. (2005). A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors. J. Biol. Chem. 280, 41655–41666.
- 459 Kash, T. L., Jenkins, A., Kelley, J. C., Trudell, J. R., and Harrison, N. L. (2003). Coupling of agonist binding to channel gating in the GABAA receptor. Nature 42, 272–275.
- 460 Kash, T. L., Dizon, M. J. F., Trudell, J. R., and Harrison, N. L. (2004). Charged residues in the β2 subunit involved in GABAA receptor activation. J. Biol. Chem. 279, 4887–4893.
- 461 Chang, Y., and Weiss, D. S. (1999). Allosteric activation mechanism of the α1β2γ2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine. Biophys. J. 77, 2542–2551.
- 462 O'Shea, S. M., and Harrison, N. L. (2000). Arg-274 and Leu-277 of the γ-aminobutyric acid type A receptor α2 subunit define agonist efficacy and potency. J. Biol. Chem. 275, 22764–22768.
- 463 Davies, M., Newell, J. G., and Dunn, S. M. (2001). Mutagenesis of the GABAA receptor alpha1 subunit reveals a domain that affects sensitivity to GABA and benzodiazepine-site ligands. J. Neurochem. 79, 55–62.
- 464 Sigel, E., Buhr, A., and Baur, R. (1999). Role of the conserved lysine residue in the middle of the predicted extracellular loop between M2 and M3 in the GABAA receptor. J. Neurochem. 73, 1758–1764.
- 465 Baur, R., and Sigel, E. (2005). Benzodiazepines affect channel opening of GABAA receptors induced by either agonist binding site. Mol. Pharmacol. 67, 1005–1008.
- 466 Thompson, S. A., Smith, M. Z., Wingrove, P. B., Whiting, P. J., and Wafford, K. A. (1999). Mutation at the putative GABAA ion-channel gate reveals changes in allosteric modulation. Br. J. Pharmacol. 127, 1349–1358.
- 467 Dalziel, J. E., Cox, G. B., Gage, P. W., and Birnir, B. (2000). Mutating the highly conserved second membrane-spanning region 9′ leucine residue in the α1 or β1 subunit produces subunit-specific changes in the function of human α1β1 γ-aminobutyric acid A receptors. Mol. Pharmacol. 57, 875–882.
- 468 Bianchi, M. T., and Macdonald, R. L. (2001). Mutation of the 9′ leucine in the GABA-A receptor γ2L subunit produces an apparent decrease in desensitization by stabilizing open states without altering desensitized states. Neuropharmacology 41, 737–744.
- 469 Jursky, F., Fuchs, K., Buhr, A., Tretter, V., Sigel, E., and Sieghart, W. (2000). Identification of amino acid residues of GABAA receptor subunits contributing to the formation and affinity of the tert-butylbicyclophosphorothionate binding site. J. Neurochem. 74, 1310–1316.
- 470 Buhr, A., Wagner, C., Fuchs, K., Sieghart, W., and Sigel, E. (2001). Two novel residues in M2 of the gamma-aminobutyric acid type A receptor affecting gating by GABA and picrotoxin affinity. J. Biol. Chem. 276, 7775–7781.
- 471 Imoto, K., Methfessel, C., Sakmann, B., Mishina, M., Mori, Y., Konno, T., Fukuda, K., Kurasaki, M., Bujo, H., and Fujita, Y. (1986). Location of a delta-subunit region determining ion transport through the acetylcholine receptor channel. Nature 324, 670–674.
- 472 Imoto, K., Busch, C., Sakmann, B., Mishina, M., Konno, T., Nakai, J., Bujo, H., Mori, Y., Fukuda, K., and Numa, S. (1988). Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature 335, 645–648.
- 473 Imoto, K., Konno, T., Nakai, J., Wang, F., Mishina, M., and Numa, S. (1991). A ring of uncharged polar amino acids as a component of channel constriction in the nicotinic acetylcholine receptor. FEBS Lett. 289, 193–200.
- 474 Imoto, K. (1993). Ion channels: Molecular basis of ion selectivity. FEBS Lett. 325, 100–103.
- 475 Jensen, M. L., Schousboe, A., and Ahring, P. K. (2005). Charge selectivity of the Cys-loop family of ligand-gated ion channels. J. Neurochem. 92, 217–225.
- 476 Wotring, V. E., Chang, Y., and Weiss, D. S. (1999). Permeability and single channel conductance of human homomeric rho1 GABAC receptors. J. Physiol. 521, 327–336.
- 477 Wotring, V. E., Miller, T. S., and Weiss, D. S. (2003). Mutations at the GABA receptor selectivity filter: A possible role for effective charges. J. Physiol. 548, 527–540.
- 478 Jensen, M. L., Timmermann, D. B., Johansen, T. H., Schousboe, A., Varming, T., and Ahring, P. K. (2002). The beta subunit determines the ion selectivity of the GABAA receptor. J. Biol. Chem. 277, 41438–41447.
- 479 Jones, M. V., and Westbrook, G. L. (1996). The impact of receptor desensitization on fast synaptic transmission. Trends Neurosci. 19, 96–101.
- 480 Overstreet, L. S., Jones, M. V., and Westbrook, G. L. (2000). Slow desensitization regulates the availability of synaptic GABAA receptors. J. Neurosci. 20, 7914–7921.
- 481 Bianchi, M. T., and Macdonald, R. L. (2002). Slow phases of GABAA receptor desensitization: Structural determinants and possible relevance for synaptic function. J. Physiol. 544, 3–18.
- 482 Jones, M. V., and Westbrook, G. L. (1995). Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15, 181–191.
- 483 Celentano, J. J., and Wong, R. K. S. (1994). Multiphasic desensitization of the GABAA receptor in outside-out patches. Biophys. J. 66, 1039–1050.
- 484 Dominguez-Perrot, C., Feltz, P., and Poulter, M. O. (1996). Recombinant GABAA receptor desensitization: The role of the γ2 subunit and its physiological significance. J. Physiol. 497, 145–159.
- 485 Haas, K. F., and Macdonald, R. L. (1999). GABAA receptor subunit γ2 and δ subtypes confer unique kinetic properties on recombinant GABAA receptors in mouse fibroblasts. J. Physiol. 514, 27–45.
- 486 Revah, F., Bertrand, D., Galzi, J. L., Devillers-Thiery, A., Mulle, C., Hussy, N., Bertrand, S., Ballivet, M., and Changeux, J. P. (1991). Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature 353, 846–849.
- 487 Yakel, J. L., Lagrutta, A., Adelman, J. P., and North, R. A. (1993). Single amino acid substitution affects desensitization kinetics of the 5-hydroxytryptamine type 3 receptor expressed in Xenopus oocytes. Proc. Nat. Acad. Sci. USA 90, 5030–5033.
- 488 Filatov, G. N., and White, M. W. (1995). The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating. Mol. Pharmacol. 48, 379–384.
- 489 Labarca, C., Nowak, M. W., Zhang, H., Tang, L., Deshpande, P., and Lester, H. A. (1995). Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors. Nature 376, 514–516.
- 490 Martinez-Torres, A., Demuro, A., and Miledi, R. (2000). GABAρ1/GABAAα1 receptor chimeras to study receptor desensitization. Proc. Nat. Acad. Sci. USA 97, 73562–73566.
- 491 Bianchi, M. T., Haas, K. F., and Macdonald, R. L. (2002). Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABAA receptors containing the delta subunit. Neuropharmacology 43, 492–502.
- 492 Bianchi, M. T., Haas, K. F., and Macdonald, R. L. (2001). Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAA receptors. J. Neurosci. 21, 1127–1136.
- 493 Scheller, M., and Forman, S. A. (2002). Coupled and uncoupled gating and desensitization effects by pore domain mutations in GABAA receptors. J. Neurosci. 22, 8411–8421.
- 494 Sternbach, L. H. (1972). The discovery of librium. Agents Actions 2, 193–196.
- 495 Sternbach, L. H. (1983). The benzodiazepine story. J. Psychoactive Drugs 15, 15–17.
- 496 Haefely, W., Facklam, M., Schoch, P., Martin, J. R., Bonetti, E. P., Moreau, J. L., Jenck, F., and Richards, J. G. (1992). GABAergic Synaptic Transmission ( G. Biggio, A. Concas A., and E. Costa, eds.). Raven, New York, pp. 379–394.
- 497 Shader, R. I., and Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders. N. Engl. J. Med. 328, 1398–1405.
- 498Mohler, H.,
Fritschy, J. M.,
Benke, D.,
Rudolph, U., and
Luscher, B.
(1996).
GABA: Receptors, Transporters and Metabolism
( C. Tanaka and
N. G. Bowery, eds.).
Bilkhauser, Basel,
pp. 157–171.
10.1007/978-3-0348-8990-2_17 Google Scholar
- 499Mohler, H.,
Fritschy, J. M.,
Luscher, B.,
Rudolph, U., and
Benson, J.
(1996).
Ion Channels,
Vol. 4
( T. Narahashi, ed.).
Plenum, New York,
pp. 89–113.
10.1007/978-1-4899-1775-1_3 Google Scholar
- 500 Yamawaki, S. (1999). The use and development of anxiolytics in Japan. Eur. J. Neuropsychopharmacol. 9, S413–S419.
- 501Sieghart, W. (2003). Handbook of Anxiety and Depression ( K. Siegfried, J. A. Boer, J. M. A. Sitsen, eds.). Marcel Dekker, New York, pp. 415–442.
- 502 Allgulander, C., Bandelow, B., Hollander, E., Montgomery, S. A., Nutt, D. J., Okasha, A., Pollack, M. H., Stein, D. J., and Swinson, R. P. (2003). World Council of Anxiety. WCA recommendations for the long-term treatment of generalized anxiety disorder. CNS Spectr. 8, 53–61.
- 503 Nemeroff, C. B. (2003). Anxiolytics: Past, present, and future agents. J. Clin. Psychiatry 64, 3–6.
- 504 Jons-Davies, D. M., and Macdonald, R. L. (2003). GABAA receptor function and pharmacology in epilepsy and status epilepticus. Curr. Opin. Pharmacol. 3, 12–18.
- 505 Haefely, W., Kulcsar, A., and Mohler, H. (1975). Possible involvement of GABA in the central actions of benzodiazepines. Psychopharmacol. Bull. 11, 58–59.
- 506 Haefely, W. E. (1977). Synaptic pharmacology of barbiturates and benzodiazepines. Agents Actions 7, 353–359.
- 507 Haefely, W. E. (1978). Central actions of benzodiazepines: General introduction. Br. J. Psychiatry 133, 231–238.
- 508 Schmidt, R. F. (1971). Presynaptic inhibition in the vertebrate central nervous system. Ergebnisse Physiol. 63, 20–101.
- 509 Mohler, H., and Okada, T. (1977). Benzodiazepine receptor: Demonstration in the central nervous system. Science 198, 849–851.
- 510 Rogers, C. J., Twyman, R. E., and MacDonald, R. L. (1994). Benzodiazepine and betacarboline regulation of single GABAA-receptor channels of mouse spinal neurons in culture. J. Physiol. 475, 69–82.
- 511 Noyes, R., Jr., Anderson, D. J., Clancy, J., Crowe, R. R., Slymen, D. J., Ghoneim, M. M., and Hinrichs, J. V. (1984). Diazepam and propranolol in panic disorder and agoraphobia. Arch. Gen. Psychiatry 41, 287–292.
- 512 Noyes, R., Jr., DuPont, R. L., Jr., Pecknold, J. C., Rifkin, A., Rubin, R. T., Swinson, R. P., Ballenger, J. C., and Burrows, G. D. (1988). Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial. II. Patient acceptance, side effects, and safety. Arch. Gen. Psychiatry 45, 423–428.
- 513 Bennett, J. A., Moioffer, M., Stanton, S. P., Dwight, M., and Keck, P. E., Jr. (1998). A risk-benefit assessment of pharmacological treatments for panic disorder. Drug Safety 18, 419–430.
- 514 Ballenger, J. C. (2001). Treatment of anxiety disorders to remission. J. Clin. Psychiatry 62, 5–9.
- 515 Atack, J. R. (2003). Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site. Curr. Drug Targets CNS Neurol. Disord. 2, 213–232.
- 516 Turski, L., Stephens, D. N., Jensen, L. H., Petersen, E. N., Meldrum, B. S., Patel, S., Hansen, J. B., Loscher, W., Schneider, H. H., and Schmiechen, R. (1990). Anticonvulsant action of the β-carboline abecarnil: Studies in rodents and baboon, Papio papio. J. Pharmacol. Exp. Ther. 253, 344–352.
- 517 Stephens, D. N., Schneider, H. H., Kehr, W., Andrews, J. S., Rettig, K. J., Turski, L., Schmiechen, R., Turner, J. D., Jensen, L. H., and Petersen, E. N., et al. (1990). Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors. J. Pharmacol. Exp. Ther. 253, 334–343.
- 518 Serra, M., Foddi, M. C., Ghiani, C. A., Melis, M. A., Motzo, C., Concas, A., Sanna, E., and Biggio, G. (1992). Pharmacology of γ-aminobutyric acid receptor complex after the in vivo administration of the anxioselective and anticonvulsant β-carboline derivative abecarnil. J. Pharmacol. Exp. Ther. 263, 1360–1368.
- 519 Serra, M., Ghiani, C. A., Motzo, C., Cuccheddu, T., Floris, S., Giusti, P., and Biggio, G. (1994). Imidazenil, a new partial agonist of benzodiazepine receptors, reverses the inhibitory action of isoniazid and stress on gamma-aminobutyric acidA receptor function. J. Pharmacol. Exp. Ther. 269, 32–38.
- 520 Serra, M., Ghiani, C. A., Motzo, C., Porceddu, M. L., and Biggio, G. (1994). Long-term treatment with abecarnil fails to induce tolerance in mice. Eur. J. Pharmacol. 259, 1–6.
- 521 Knoflach, F., Drescher, U., Scheurer, L., Malherbe, P., and Mohler, H. (1993). Full and partial agonism displayed by benzodiazepine receptor ligands at recombinant γ-aminobutyric acid receptor subtypes. J. Pharmacol. Exp. Ther. 266, 385–391.
- 522 Ozawa, M., Sugimachi, K., Nakada-Kometani, Y., Akai, T., and Yamaguchi, M. (1994). Chronic pharmacological activities of the novel anxiolytic β-carboline abecarnil in rats. J. Pharmacol. Exp. Ther. 269, 457–462.
- 523 Ozawa, M., Nakada, Y., Sugimachi, K., Yabuuchi, F., Akai, T., Mizuta, E., Kuno, S., and Yamaguchi, M. (1994). Pharmacological characterization of the novel anxiolytic β-carboline abecarnil in rodents and primates. Jpn. J. Pharmacol. 64, 179–187.
- 524 Pollack, M. H., Worthington, J. J., Manfro, G. G., Otto, M. W., and Zucker, B. G. (1997). Abecarnil for the treatment of generalized anxiety disorder: A placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. J. Clin. Psychiatry 58, 19–23.
- 525 Haigh, J. R. M., and Feely, M. (1988). Ro 16-6028, a benzodiazepine receptor partial agonist, does not exhibit anticonvulsant tolerance in mice. Eur. J. Pharmacol. 147, 283–285.
- 526 Martin, J. R., Pieri, L., Bonetti, E. P., Schaffner, R., Burkard, W. P., Cumin, R., and Haefely, W. (1988). Ro 16-6028: A novel anxiolytic acting as a partial agonist at the benzodiazepine receptor. Pharmacopsychiatry 21, 360–362.
- 527 Potier, M. C., de Carvalho, L. P., Venault, P., Chapouthier, G., and Rossier, J. (1988). Demonstration of the partial agonist profiles of Ro 16-6028 and Ro 17-1812 in mice in vivo. Eur. J. Pharmacol. 156, 169–172.
- 528 Moreau, J. L., Jenck, F., Pieri, L., Schoch, P., Martin, J. R., and Haefely, W. E. (1990). Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by partial agonist Ro16-6028. Eur. J. Pharmacol. 190, 269–273.
- 529 Puia, G., Ducic, I., Vicini, S., and Costa, E. (1992). Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at γ-aminobutyric acid type A receptor. Proc. Nat. Acad. Sci. USA 89, 3620–3624.
- 530 Delini-Stula, A., and Berdah-Tordjman, D. (1996). Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report. J. Psychiatric Res. 30, 239–250.
- 529a Finn, D. A., and Gee, K. W. (1993). A comparison of Ro 16-6028 with benzodiazepine receptor “full agonists” on GABA receptor function. Eur. J. Pharmacol. 247, 233–237.
- 532 Bronson, M. E. (1994). Chlordiazepoxide, but not bretazenil, produces acute dependence, as evidenced by disruptions in schedule-controlled behavior. Pharmacol. Biochem. Behav. 48, 397–401.
- 533 Gardner, C. R., Deacon, R., Guy, A. P., Mann, R., Budhram, P., and Miller, P. (1987). RU 32698, a new benzodiazepine receptor ligand with anxiolytic but little sedative and myorelaxant properties. Br. J. Pharmacol. 92, 537P.
- 534 Feely, M., Boyland, P., Picardo, A., Cox, A., and Gent, J. P. (1989). Lack of anticonvulsant tolerance with RU 32698 and Ro 17-1812. Eur. J. Pharmacol. 164, 377–380.
- 535 James, V., and Gardner, C. R. (1991). Reversal of stress-induced arousal in sleeping rats by some imidazopyrimidine benzodiazepine receptor ligands. Drug Dev. Res. 22, 331–337.
- 536 Giusti, P., Ducic, I., Puia, G., Arban, R., Walser, A., Guidotti, A., and Costa, E. (1993). Imidazenil: A new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. J. Pharmacol. Exp. Ther. 266, 1018–1028.
- 537 Auta, J., Giusti, P., Guidotti, A., and Costa, E. (1994). Imidazenil, a partial positive allosteric modulator of GABA receptors, exhibits low tolerance and dependence liabilities in the rat. J. Pharmacol. Exp. Ther. 270, 1262–1269.
- 538 Ghiani, C. A., Serra, M., Motzo, C., Giusti, P., Cuccheddu, T., Porceddu, M. L., and Biggio, G. (1994). Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice. Eur. J. Pharmacol. 254, 299–302.
- 539 Dazzi, L., Motzo, C., Imperato, A., Serra, M., Gessa, G. L., and Biggio, G. (1995). Modulation of basal and stress-induced release of acetylcholine and dopamine in rat brain by abecarnil and imidazenil, two anxioselective γ-aminobutyric acid receptor modulators. J. Pharmacol. Exp. Ther. 273, 241–247.
- 540 Thompson, D. M., Auta, J., Guidotti, A., and Costa, E. (1995). Imidazenil, a new anxiolytic and anti-convulsant drug, attenuates a benzodiazepine-induced cognition deficit in monkeys. J. Pharmacol. Exp. Ther. 273, 1307–1312.
- 541 Patat, A., Paty, I., and Hindmarch, I. (2001). Pharmacodynamic profile of zaleplon, a new non-benzodiazepine hypnotic agent. Hum. Psychopharmacol. Clin. Exp. 16, 369–392.
- 542 Drover, D. R. (2004). Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: Zaleplon, zolpidem and zopiclone. Clin. Pharmacokinet. 43, 227–238.
- 543
Langer, S. Z.,
Faure-Halley, C.,
Seeburg, P.,
Graham, D., and
Arbilla, S.
(1992).
The selectivity of zolpidem and alpidem for the α1-subunit of the GABAA receptor.
Eur. Neuropsychopharmacol.
2,
232–234.
10.1016/0924-977X(92)90081-I Google Scholar
- 544 Sanger, D. J., Morel, E., and Perrault, G. (1996). Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. Eur. J. Pharmacol. 313, 35–42.
- 545 Jensen, L. H., and Petersen, E. N. (1983). Bidirectional effects of benzodiazepine receptor ligands against picrotoxin- and pentylenetetrazol-induced seizures. J. Neural Transmiss. 58, 183–191.
- 546 Facklam, M., Schoch, P., Bonetti, E. P., Jenck, F., Martin, J. R., Moreau, J. L., and Haefely, W. E. (1992). Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies. J. Pharmacol. Exp. Ther. 261, 1113–1121.
- 547 Gasior, M., Ungard, J. T., Beekman, M., Carter, R. B., and Witkin, J. M. (2000). Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: Comparison with diazepam and valproate. Neuropharmacology 39, 1184–1196.
- 548 Cole, J. C., and Rodgers, R. J. (1993). An ethological analysis of the effects of chlordiazepoxide and bretazenil (Ro 16-6028) in the murine elevated plus-maze. Behav. Pharmacol. 4, 573–580.
- 549 Khanna, J. M., Kalant, H., Chau, A., and Shah, G. (1998). Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol. Pharmacol. Biochem. Behav. 59, 511–519.
- 550 Busto, U., Kaplan, H. L., Zawertailo, L., and Sellers, E. M. (1994). Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans. Clin. Pharmacol. Ther. 55, 451–463.
- 551 Damgen, K., and Luddens, H. (1999). Zaleplon displays a selectivity to recombinant GABAA receptors different from zolpidem, zopiclone and benzodiazepines. Neurosci. Res. Commun. 25, 139–148.
- 552 Hood, S. D., Argyropoulos, S. V., and Nutt, D. J. (2000). Agents in development for anxiety disorders. Current status and future potential. CNS Drugs 13, 421–431.
- 553 Griebel, G., Perrault, G., Simiand, J., Cohen, C., Granger, P., Decobert, M., Francon, D., Avenet, P., Depoortere, H., Tan, S., Oblin, A., Schoemaker, H., Evanno, Y., Sevrin, M., George, P., and Scatton, B. (2001). SL651498: An anxioselective compound with functional selectivity for α2 and α3 containing gamma-aminobutyric acidA receptors. J. Pharmacol. Exp. Ther. 98, 753–768.
- 554 Griebel, G., Perrault, G., Simiand, J., Cohen, C., Granger, P., Depoortere, H., Francon, D., Avenet, P., Schoemaker, H., Evanno, Y., Sevrin, M., George, P., and Scatton, B. (2003). SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. CNS Drug Rev. 9, 3–20.
- 555 Scatton, B., Depoortere, H., George, P., Sevrin, M., Benavides, J., Schoemaker, H., and Perrault, G. (2000). Selectivity for GABAA receptor α subunits as a strategy for developing hypnoselective and anxioselective drugs. Int. J. Neuropsychopharmacol. 3, S413.
- 556 Li, X., Cao, H., Zhang, C., Furtmueller, R., Fuchs, K., Huck, S., Sieghart, W., Deschamps, J., and Cook, J. M. (2003). Synthesis, in vitro affinity, and efficacy of a bis 8-ethynyl-4H-imidazo[1,5a]-[1,4]benzodiazepine analogue, the first bivalent α5 subtype selective BZR/GABAA antagonist. J. Med. Chem. 46, 5567–5570.
- 554a Quirk, K., Blurton, P., Fletcher, S., Leeson, P., Tang, F., Mellilo, D., Ragan, C. I., and McKernan, R. M. (1996). [3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the α5 subunit. Neuropharmacology 35, 1331–1335.
- 558 Chambers, M. S., Atack, J. R., Bromidge, F. A., Broughton, B. H., Cook, S., Dawson, G. R., Hobbs, S. C., Maubach, K. A., Reeve, A. J., Seabrook, G. R., Wafford, K., and MacLeod, A. M. (2002). 6,7-Dihydro-2-benzothiophen-4(5H)-ones: A novel class of GABA-A α5 receptor inverse agonists. J. Med. Chem. 45, 1176–1179.
- 559 Chambers, M. S., Atack, J. R., Broughton, H. B., Collinson, N., Cook, S., Dawson, G. R., Hobbs, S. C., Marshall, G., Maubach, K. A., Pillai, G. V., Reeve, A. J., and MacLeod, A. M. (2003). Identification of a novel, selective GABAA α5 receptor inverse agonist which enhances cognition. J. Med. Chem. 46, 2227–2240.
- 560 Medina, J. H., Viola, H., Wolfman, C., Marder, M., Wasowski, C., Calvo, D., and Paladini, A. C. (1997). Overview of flavonoids: A new family of benzodiazepine receptor ligands. Neurochem. Res. 22, 419–425.
- 561 Medina, J. H., Pena, C., Levi de Stein, M., Wolfman, C., and Paladini, A. C. (1989). Benzodiazepine-like molecules, as well as other ligands for the brain benzodiazepine receptors, are relatively common constituents of plants. Biochem. Biophys. Res. Commun. 165, 547–553.
- 562 Medina, J. H., Paladini, A. C., Wolfman, C., Levi de Stein, M., Calvo, D., Diaz, L. E., and Pena, C. (1990). Chrysin (5,7-di-OH-flavone), a naturally-occurring ligand for benzodiazepine receptors, with anticonvulsant properties. Biochem. Pharmacol. 40, 2227–2231.
- 563 Wolfman, C., Viola, H., Paladini, A., Dajas, F., and Medina, J. H. (1994). Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea. Pharmacol. Biochem. Behav. 47, 1–4.
- 564 Huen, M. S., Hui, K. M., Leung, J. W., Sigel, E., Baur, R., Wong, J. T., and Xue, H. (2003). Naturally occurring 2′-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands. Biochem. Pharmacol. 66, 2397–2407.
- 565 Kavvadias, D., Sand, P., Youdim, K. A., Qaiser, M. Z., Rice-Evans, C., Baur, R., Sigel, E., Rausch, W. D., Riederer, P., and Schreier, P. (2004). The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects. Br. J. Pharmacol. 142, 811–820.
- 566 Hui, K. M., Wang, X. H., and Xue, H. (2000). Interaction of flavones from the roots of Scutellaria baicalensis with the benzodiazepine site. Planta Med. 66, 91–93.
- 567 Hui, K. M., Huen, M. S., Wang, H. Y., Zheng, H., Sigel, E., Baur, R., Ren, H., Li, Z. W., Wong, J. T., and Xue, H. (2002). Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem. Pharmacol. 64, 1415–1424.
- 568 Nielsen, M., Frokjaer, S., and Braestrup, C. (1988). High affinity of the naturally occurring biflavonoid, amentoflavon, to brain benzodiazepine receptors in vitro. Biochem. Pharmacol. 37, 3285–3287.
- 569 Haberlein, H., Tschiersch, K. P., and Schafer, H. L. (1994). Flavonoids from Leptospermum scoparium with affinity to the benzodiazepine receptor characterized by structure activity relationships and in vivo studies of a plant extract. Pharmazie 49, 912–922.
- 570 Wolfman, C., Viola, H., Marder, M., Wasowski, C., Ardenghi, P., Izquierdo, I., Paladini, A. C., and Medina, J. H. (1996). Anxioselective properties of 6,3′-dinitroflavone a high-affinity benzodiazepine receptor ligand. Eur. J. Pharmacol. 318, 23–30.
- 571 Goutman, J. D., Waxemberg, M. D., Donate-Oliver, F., Pomata, P. E., and Calvo, D. J. (2003). Flavonoid modulation of ionic currents mediated by GABAA and GABAC receptors. Eur. J. Pharmacol. 461, 79–87.
- 572 Dekermendjian, K., Kahnberg, P., Witt, M. R., Sterner, O., Nielsen, M., and Liljefors, T. (1999). Structure–activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABAA receptor complex. J. Med. Chem. 42, 4343–4350.
- 573 Huang, X., Liu, T., Gu, J., Luo, X., Ji, R., Cao, Y., Xue, H., Wong, J. T., Wong, B. L., Pei, G., Jiang, H., and Chen, K. (2001). 3D-QSAR model of flavonoids binding at benzodiazepine site in GABAA receptors. J. Med. Chem. 44, 1883–1891.
- 574 Kahnberg, P., Lager, E., Rosenberg, C., Schougaard, J., Camet, L., Sterner, O. O., Nielsen, E., Nielsen, M., and Liljefors, T. (2002). Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABAA receptor. J. Med. Chem. 45, 4188–4201.
- 575 Hong, X., and Hopfinger, A. J. (2003). 3D-pharmacophores of flavonoid binding at the benzodiazepine GABAA receptor site using 4D-QSAR analysis. J. Chem. Informatics Computer Sci. 43, 324–326.
- 576 Ai, J. D. K., Wnag, X., Nielsen, M., and Witt, M. R. (1997). 6-Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABAA receptors in vitro. Drug Dev. Res. 41, 99–106.
- 577 Viola, H., Wolfman, C., Marder, M., Goutman, J. D., Bianchin, M., Wasowski, C., Calvo, D. J., Izquierdo, I., Paladini, A. C., and Medina, J. H. (2000). 6-Chloro-3′-nitroflavone is a potent ligand for the benzodiazepine binding site of the GABAA receptor devoid of intrinsic activity. Pharmacol. Biochem. Behav. 65, 313–320.
- 578 Viola, H., Marder, M., Wasowski, C., Giorgi, O., Paladini, A. C., and Medina, J. H. (2000). 6,3′-Dibromoflavone and 6-nitro-3′-bromoflavone: New additions to the 6,3′-disubstituted flavone family of high-affinity ligands of the brain benzodiazepine binding site with agonistic properties. Biochem. Biophys. Res. Commun. 273, 694–698.
- 579 Wang, H., Hui, K. M., Chen, Y., Xu, S., Wong, J. T., and Xue, H. (2002). Structure–activity relationships of flavonoids, isolated from Scutellaria baicalensis binding to benzodiazepine site of GABAA receptor complex. Planta Med. 68, 1059–1062.
- 580 Papadopoulos, V., Amri, H., Li, H., Yao, Z., Brown, R. C., Vidic, B., and Culty, M. (2001). Structure, function and regulation of the mitochondrial peripheral-type benzodiazepine receptor. Therapie 56, 549–556.
- 581 Casalotti, S. O., Stephenson, A., and Barnard, E. A. (1986). Separate subunits for agonist and benzodiazepine binding in the γ-aminobutyric acidA receptor oligomer. J. Biol. Chem. 261, 15013–15016.
- 582 Deng, L., Ransom, R. W., and Olsen, R. W. (1986). [3H]Muscimol photolabels the γ-aminobutyric acid receptor binding site on a peptide subunit distinct from that labelled with benzodiazepine. Biochem. Biophys. Res. Commun. 138, 1308–1314.
- 583 Pritchett, D. B., Luddens, H., and Seeburg, P. H. (1989). Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245, 1389–1392.
- 584 Smith, G. B., and Olsen, R. W. (1995). Functional domains of GABAA receptors. Trends Pharmacol. Sci. 16, 162–168.
- 585 Sigel, E., and Buhr, A. (1997). The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425–429.
- 586 Smith, A. J., Alder, L., Silk, J., Adkins, C., Fletcher, A. E., Scales, T., Kerby, J., Marshall, G., Wafford, K. A., McKernan, R. M., and Atack, J. R. (2001). Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acidA receptors determined using 36Cl ion flux. Mol. Pharmacol. 59, 1108–1118.
- 587 Mohler, H., Battersby, M. K., and Richards, J. G. (1980). Benzodiazepine receptor protein identified and visualized in brain tissue by a photoaffinity label. Proc. Nat. Acad. Sci. USA 77, 1666–1670.
- 588 Fuchs, K., Mohler, H., and Sieghart, W. (1988). Various proteins from rat brain, specifically and irreversibly labeled by [3H]flunitrazepam, are distinct alpha-subunits of the GABA-benzodiazepine receptor complex. Neurosci. Lett. 90, 314–319.
- 589 Stephenson, F. A., Duggan, M. J., and Pollard, S. (1990). The γ2 subunit is an integral component of the γ-aminobutyric acidA receptor but the alpha1 polypeptide is the principal site of the agonist benzodiazepine photoaffinity labeling reaction. J. Biol. Chem. 265, 21160–21165.
- 590 McKernan, R. M., Wafford, K., Quirk, K., Hadingham, K. L., Harley, E. A., Ragan, C. I., and Whiting, P. J. (1995). The pharmacology of the benzodiazepine site of the GABAA receptor is dependent upon the type of γ-subunit present. J. Receptor Signal Transduct. Res. 15, 173–183.
- 591 Davies, M., Martin, I. L., Bateson, A. N., Hadingham, K. L., Whiting, P. J., and Dunn, S. M. (1996). Identification of domains in human recombinant GABAA receptors that are photoaffinity labelled by [3H]flunitrazepam and [3H]Ro15-4513. Neuropharmacology 35, 1199–1208.
- 592 Davies, M., and Dunn, S. M. (1998). Identification of a unique domain in bovine brain GABAA receptors that is photoaffinity labelled by [3H]Ro15-4513. Biochem. Biophys. Res. Commun. 246, 650–653.
- 593 Sawyer, G. W., Chiara, D. C., Olsen, R. W., and Cohen, J. B. (2002). Identification of the bovine gamma-aminobutyric acid type A receptor alpha subunit residues photolabeled by the imidazobenzodiazepine [3H]Ro15-4513. J. Biol. Chem. 277, 50036–50045.
- 594 Smith, G. B., and Olsen, R. W. (2000). Deduction of amino acid residues in the GABAA receptor alpha subunits photoaffinity labeled with the benzodiazepine flunitrazepam. Neuropharmacology 39, 55–64.
- 595 Duncalfe, L. L., and Dunn, S. M. (1996). Mapping of GABAA receptor sites that are photoaffinity-labelled by [3H]flunitrazepam and [3H]Ro 15-4513. Eur. J. Pharmacol. 298, 313–319.
- 596 Duncalfe, L. L., Carpenter, M. R., Smillie, L. B., Martin, I. L., and Dunn, S. M. (1996). The major site of photoaffinity labeling of the gamma-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the alpha subunit. J. Biol. Chem. 271, 9209–9214.
- 597 Wieland, H. A., Luddens, H., and Seeburg, P. H. (1992). A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 267, 1426–1429.
- 598 Wieland, H. A., and Luddens, H. (1994). Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. J. Med. Chem. 37, 4576–4580.
- 599 Pritchett, D. B., and Seeburg, P. H. (1991). Gamma-aminobutyric acid type A receptor point mutation increases the affinity of compounds for the benzodiazepine site. Proc. Nat. Acad. Sci. USA 88, 1421–1425.
- 600 Schaerer, M. T., Buhr, A., Baur, R., and Sigel, E. (1998). Amino acid residue 200 on the alpha1 subunit of GABAA receptors affects the interaction with selected benzodiazepine binding site ligands. Eur. J. Pharmacol. 354, 283–287.
- 601 Wingrove, P. B., Safo, P., Wheat, L., Thompson, S. A., Wafford, K. A., and Whiting, P. J. (2002). Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur. J. Pharmacol. 437, 31–39.
- 602 Casula, M. A., Bromidge, F. A., Pillai, G. V., Wingrove, P. B., Martin, K., Maubach, K., Seabrook, G. R., Whiting, P. J., and Hadingham, K. L. (2001). Identification of amino acid residues responsible for the alpha5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABAA receptor. J. Neurochem. 77, 445–451.
- 603 Strakhova, M. I., Harvey, S. C., Cook, C. M., Cook, J. M., and Skolnick, P. (2000). A single amino acid residue on the alpha5 subunit (Ile215) is essential for ligand selectivity at α5β3γ2 gamma-aminobutyric acidA receptors. Mol. Pharmacol. 58, 1434–1440.
- 604 Kucken, A. M., Wagner, D. A., Ward, P. R., Teissere, J. A., Boileau, A. J., and Czajkowski, C. (2000). Identification of benzodiazepine binding site residues in the γ2 subunit of the gamma-aminobutyric acidA receptor. Mol. Pharmacol. 57, 932–939.
- 605 Wingrove, P. B., Thompson, S. A., Wafford, K. A., and Whiting, P. J. (1997). Key amino acids in the γ subunit of the γ-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site. Mol. Pharmacol. 52, 874–881.
- 606 Sigel, E., Schaerer, M. T., Buhr, A., and Baur, R. (1998). The benzodiazepine binding pocket of recombinant α1β2γ2 gamma-aminobutyric acidA receptors: Relative orientation of ligands and amino acid side chains. Mol. Pharmacol. 54, 1097–1105.
- 607 Mihic, S. J., Whiting, P. J., Klein, R. L., Wafford, K. A., and Harris, R. A. (1994). A single amino acid of the human gamma-aminobutyric acid type A receptor γ2 subunit determines benzodiazepine efficacy. J. Biol. Chem. 269, 32768–32773.
- 608 Malminiemi, O., and Korpi, E. R. (1989). Diazepam-insensitive [3H]Ro15-4513 binding in intact cultured cerebellar granule cells. Eur. J. Pharmacol. 169, 53–60.
- 609 Hadingham, K. L., Garrett, E. M., Wafford, K. A., Bain, C., Heavens, R. P., Sirinathsinghji, D. S., and Whiting, P. J. (1996). Cloning of cDNA encoding the human γ-aminobutyric acidA receptor α6 subunit and characterization of the pharmacology of α6-containing receptors. Mol. Pharmacol. 49, 253–259.
- 610 Knoflach, F., Benke, D., Wang, Y., Scheurer, L., Luddens, H., Hamilton, B. J., Carter, D. B., Mohler, H., and Benson, J. A. (1996). Pharmacological modulation of the diazepam insensitive recombinant γ-aminobutyric acid A receptors α4β2γ2 and α6β2γ2. Mol. Pharmacol. 50, 1243–1261.
- 611 Pritchett, D. B., and Seeburg, P. H. (1990). Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. 54, 1802–1804.
- 612 Yang, W., Drewe, J. A., and Lan, N. C. (1995). Cloning and characterization of the human GABAA receptor a4 subunit: Identification of a unique diazepam-insensitive binding site. Eur. J. Pharmacol. 209, 319–325.
- 613 Street, L. J., Sternfeld, F., Jelley, R. A., Reeve, A. J., Carling, R. W., Moore, K. W., McKernan, R. M., Sohal, B., Cook, S., Pike, A., Dawson, G. R., Bromidge, F. A., Wafford, K. A., Seabrook, G. R., Thompson, S. A., Marshall, G., Pillai, G. V., Castro, J. L., Atack, J. R., and MacLeod, A. M. (2004). Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABAA alpha5 benzodiazepine binding site. J. Med. Chem. 47, 3642–3657.
- 614 Huang, Q., He, X., Ma, C., Liu, R., Yu, S., Dayer, C. A., Wenger, G. R., McKernan, R., and Cook, J. M. (2000). Pharmacophore/receptor models for GABAA/BzR subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a comprehensive ligand-mapping approach. J. Med. Chem. 43, 71–95.
- 615 Gunnersen, D., Kaufman, C. M., and Skolnick, P. (1996). Pharmacological properties of recombinant “diazepam-insensitive” GABAA receptors. Neuropharmacology 35, 1307–1314.
- 616 Wafford, K. A., Whiting, P. J., and Kemp, J. A. (1993). Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes. Mol. Pharmacol. 43, 240–244.
- 617 Szekeres, H. J., Atack, J. R., Chambers, M. S., Cook, S. M., Macaulay, A. J., Pillai, G. V., and MacLeod, A. M. (2004). 3,4-Dihydronaphthalen-1(2H)-ones: Novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors. Bioorg. Med. Chem. Lett. 14, 2871–2875.
- 618 Hadingham, K. L., Wafford, K. A., Thompson, S. A., Palmer, K. J., and Whiting, P. J. (1995). Expression and pharmacology of human GABAA receptors containing γ3 subunits. Eur. J. Pharmacol. 291, 301–309.
- 619 Puia, G., Vicini, S., Seeburg, P. H., and Costa, E. (1991). Influence of recombinant γ-aminobutyric acidA receptor subunit composition on the action of allosteric modulators of γ-aminobutyric acid-gated Cl− currents. Mol. Pharmacol. 39, 691–696.
- 620 Herb, A., Wisden, W., Luddens, H., Puia, G., Vicini, S., and Seeburg, P. H. (1992). The third γ-subunit of the γ-aminobutyric acid type A receptor family. Proc. Nat. Acad. Sci. USA 88, 1433–1437.
- 621 Ducic, I., Puia, G., Vicini, S., and Costa, E. (1993). Triazolam is more efficacious than diazepam in a broad spectrum of recombinant GABAA receptors. Eur. J. Pharmacol. 244, 29–35.
- 622 Petroski, R. E., Pomeroy, J. E., Das, R., Bowman, H., Yang, W., Chen, A. P., and Foster, A. C. (2006). Indiplon is a high-affinity positive allosteric modulator with selectivity for α1 subunit containing GABAA receptors. J. Pharmacol. Exp. Ther. 317, 369–377.
- 623 Luddens, H., Seeburg, P. H., and Korpi, E. R. (1994). Impact of α and γ variants on ligand-binding properties of γ-aminobutyric acid type A receptors. Mol. Pharmacol. 45, 810–814.
- 624 Davies, M., Newell, J. G., Derry, J. M., Martin, I. L., and Dunn, S. M. (2000). Characterization of the interaction of zopiclone with gamma-aminobutyric acid type A receptors. Mol. Pharmacol. 58, 756–762.
- 625 Khom, S., Baburin, I., Timin, E. N., Hohaus, A., Sieghart, W., and Hering, S. (2006). Pharmacological properties of GABAA receptors containing gamma1 subunits. Mol. Pharmacol. 69, 640–649.
- 626 Renard, S., Olivier, A., Granger, P., Avenet, P., Graham, D., Sevrin, M., George, P., and Besnard, F. (1999). Structural elements of the gamma-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands. J. Biol. Chem. 274, 13370–13374.
- 627 Sancar, F., Ericksen, S. S., Kucken, A. M., Teissere, J. A., and Czajkowski, C. 2006.. Structural determinants for high affinity zolpidem binding to GABAA receptors. Mol. Pharmacol. In press.
- 628 Derry, J. M., Dunn, S. M., and Davies, M. (2004). Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding. J. Neurochem. 88, 1431–1438.
- 629 Ymer, S., Draguhn, A., Wisden, W., Werner, P., Keinanen, K., Schofield, P. R., Sprengel, R., Pritchett, D. B., and Seeburg, P. H. (1990). Structural and functional characterization of the γ1-subunit of GABAA benzodiazepine receptors. EMBO J. 9, 3261–3267.
- 630 Harrison, N. L., and Simmonds, M. A. (1984). Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res. 323, 287–292.
- 631 Puia, G., Santi, M. R., Vicini, S., Pritchett, D. B., Purdy, R. H., Paul, S. M., Seeburg, P. H., and Costa, E. (1990). Neurosteroids act on recombinant human GABAA receptor. Neuron 4, 759–765.
- 632 Zaman, S. H., Shingai, R., Harvey, R. J., Darlinson, M. G., and Barnard, E. A. (1992). Effects of subunit types of the recombinant GABAA receptor on the response to a neurosteroid. Eur. J. Pharmacol. 225, 321–330.
- 633 Park-Chung, M., Malayev, A., Purdy, R. H., Gibbs, T. T., and Farb, D. H. (1999). Sulfated and unsulfated steroids modulate γ-aminobutyric acidA receptor function through distinct sites. Brain Res. 830, 72–87.
- 634 Akk, G., Bracamontes, J., and Steinbach, J. H. (2001). Pregnenolone sulfate block of GABAA receptors: Mechanism and involvement of a residue in the M2 region of the alpha subunit. J. Physiol. 532, 673–684.
- 635 Lambert, J. J., Belelli, D., Harney, S. C., Peters, J. A., and Frenguelli, B. G. (2001). Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids. Brain Res. Rev. 37, 68–80.
- 636 Belelli, D., Lambert, J. J., Peters, J. A., Wafford, K., and Whiting, P. J. (1997). The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proc. Nat. Acad. Sci. USA 94, 11031–11036.
- 637 Hill-Venning, C., Belelli, D., Peters, J. A., and Lambert, J. J. (1997). Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br. J. Pharmacol. 120, 749–756.
- 638 Belelli, D., Pau, D., Cabras, G., Peters, J. A., and Lambert, J. J. (1999). A single amino acid confers barbiturate sensitivity upon the GABA rho 1 receptor. Br. J. Pharmacol. 27, 601–604.
- 639 Belelli, D., Pistis, I., Peter, J. A., and Lambert, J. J. (1999). General anaesthetic action at transmitter-gated inhibitory amino acid receptors. Trends Pharmacol. Sci. 20, 496–502.
- 640 Krasowski, M. D., Jenkins, A., Flood, P., Kung, A. Y., Hopfinger, A. J., and Harrison, N. L. (2001). General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABAA receptor but not with lipid solubility. J. Pharmacol. Exp. Ther. 297, 338–351.
- 641 Krasowski, M. D., Nishikawa, K., Nikolaeva, N., Lin, A., and Harrison, N. L. (2001). Methionine 286 in transmembrane domain 3 of the GABAA receptor beta subunit controls a binding cavity for propofol and other alkylphenol general anesthetics. Neuropharmacology 41, 952–964.
- 642 Korpi, E. R., Grunder, G., and Luddens, H. (2002). Drug interactions at GABAA receptors. Prog. Neurobiol. 67, 113–159.
- 643 Siegwart, R., Jurd, R., and Rudolph, U. (2002). Molecular determinants for the action of general anesthetics at recombinant α2β3γ2 gamma-aminobutyric acidA receptors. J. Neurochem. 80, 140–148.
- 644 Bali, M., and Akabas, M. H. (2004). Defining the propofol binding site location on the GABAA receptor. Mol. Pharmacol. 65, 68–76.
- 645 Wick, M. J., Mihic, S. J., Ueno, S., Mascia, M. P., Trudell, J. R., Brozowski, S. J., Ye, Q., Harrison, N. L., and Harris, R. A. (1998). Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: Evidence for an alcohol receptor? Proc. Nat. Acad. Sci. USA 95, 6504–6509.
- 646 Ueno, S., Wick, M. J., Ye, Q., Harrison, N. L., and Harris, R. A. (1999). Subunit mutations affect ethanol actions on GABAA receptors expressed in Xenopus oocytes. Br. J. Pharmacol. 127, 377–382.
- 647 Mascia, M. P., Trudell, J. R., and Harris, R. A. (2000). Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc. Nat. Acad. Sci. USA 97, 9305–9310.
- 648 Ueno, S., Lin, A., Nikolaeva, N., Trudell, J. R., Mihic, S. J., Harris, R. A., and Harrison, N. L. (2000). Tryptophan scanning mutagenesis in TM2 of the GABAA receptor alpha subunit: Effects on channel gating and regulation by ethanol. Br. J. Pharmacol. 131, 296–302.
- 649 Vaught, K. A., and Wauquier, A. (1991). Evidence for a unique interaction of loreclezole with the GABA receptor complex. Drug Dev. Res. 23, 181–189.
- 650 Wafford, K. A., Bain, C. J., Quirk, K., McKernan, R. M., Wingrove, P. B., Whiting, P. J., and Kemp, J. A. (1994). A novel allosteric modulatory site on the GABAA receptor β subunit. Neuron 12, 775–782.
- 651 Green, A. R., Misra, A., Murray, T. K., Snape, M. F., and Cross, A. J. (1996). A behavioural and neurochemical study in rats of Loreclezole, a novel allosteric modulator of the GABAA receptor. Neuropharmacology 35, 1243–1250.
- 652 Servant, D., Graziani, P. L., Moyse, D., and Parquet, P. J. (1998). Traitement du trouble de l′adaptation avec anxiete: Evaluation de l′efficacite et de la tolerance de l′etifoxine par un essai en double aveugle contre produit de reference. Encephale 24, 569–574.
- 653 Micallef, J., Soubrouillard, C., Guet, F., Le Guern, M. E., Alquier, C., Bruguerolle, B., and Blin, O. (2001). A double blind parallel group placebo controlled comparison of sedative and amnesic effects of etifoxine and lorazepam in healthy subjects. Fund. Clin. Pharmacol. 15, 209–216.
- 654 Thompson, S. A., Wingrove, P. B., Connelly, L., Whiting, P. J., and Wafford, K. A. (2002). Tracazolate reveals a novel type of allosteric interaction with recombinant gamma-aminobutyric acidA receptors. Mol. Pharmacol. 61, 861–869.
- 655 Korpi, E. R., Kuner, T., Seeburg, P. H., and Luddens, H. (1995). Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor. Mol. Pharmacol. 47, 283–289.
- 656 Thompson, S. A., Arden, S. A., Marshall, G., Wingrove, P. B., Whiting, P. J., and Wafford, K. A. (1999). Residues in transmembrane domains I and II determine γ-aminobutyric acid type A receptor subtype-selective antagonism by furosemide. Mol. Pharmacol. 55, 993–999.
- 657 Fisher, J. L. (2002). Amiloride inhibition of gamma-aminobutyric acidA receptors depends upon the alpha subunit subtype. Mol. Pharmacol. 61, 1322–1328.
- 658 Selye, H. (1970). Adaptive steroids: Retrospect and prospect. Perspect. Biol. Med. 13, 343–363.
- 659 Paul, S. M., and Purdy, R. H. (1992). Neuroactive steroids. FASEB J. 6, 2311–2322.
- 660 Reddy, D. S. (2003). Pharmacology of endogenous neuroactive steroids. Crit. Rev. Neurobiol. 15, 197–234.
- 661 Baulieu, E. E., and Robel, P. (1990). Neurosteroids: A new brain function. J. Steroid Biochem. Mol. Biol. 37, 395–403.
- 662 Lambert, J. J., Belelli, D., Hill-Venning, C., and Peters, J. A. (1995). Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 16, 295–303.
- 663 Gee, K. W., and Lan, N. C. (1991). γ-Aminobutyric acidA receptor complexes in rat cortex and spinal cord show differential responses to steroid modulation. Mol. Pharmacol. 40, 995–999.
- 664 Majewska, M. D., Mienville, J. M., and Vicini, S. (1988). Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons. Neurosci. Lett. 90, 279–284.
- 665 Zhu, W. J., and Vicini, S. (1997). Neurosteroid prolongs GABAA channel deactivation by altering kinetics of desensitized states. J. Neurosci. 17, 4022–4031.
- 666 Shen, W., Mennerick, S., Covey, D. F., and Zorumski, C. F. (2000). Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABAA receptor desensitization. J. Neurosci. 20, 3571–3579.
- 667 Bitran, D., Hilvers, R. J., and Kellogg, C. K. (1991). Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: Endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res. 561, 157–161.
- 668 Melchior, C. L., and Ritzmann, R. (1994). Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze. Pharmacol. Biochem. Behav. 48, 893–897.
- 669 Finn, D. A., Roberts, A. J., Long, S., Tanchuck, M., and Phillips, T. J. (2003). Neurosteroid consumption has anxiolytic effects in mice. Pharmacol. Biochem. Behav. 76, 451–462.
- 670 Gasior, M., Carter, R. B., and Witkin, J. M. (1999). Neuroactive steroids: Potential therapeutic use in neurological and psychiatric disorders. Trends Pharmacol. Sci. 20, 107–112.
- 671 Gasior, M., Carter, R. B., Goldberg, S. R., and Witkin, J. M. (1997). Anticonvulsant and behavioral effects of neuroactive steroids alone and in conjunction with diazepam. J. Pharmacol. Exp. Ther. 282, 543–553.
- 672 Reddy, D. S., and Rogawski, M. A. (2000). Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J. Pharmacol. Exp. Ther. 295, 1241–1248.
- 673 Beekman, M., Ungard, J. T., Gasior, M., Carter, R. B., Dijkstra, D., Goldberg, S. R., and Witkin, J. M. (1998). Reversal of behavioral effects of pentylenetetrazol by the neuroactive steroid ganaxolone. J. Pharmacol. Exp. Ther. 284, 868–877.
- 674 Wieland, S., Belluzzi, J., Hawkinson, J. E., Hogenkamp, D., Upasani, R., Stein, L., Wood, P. L., Gee, K. W., and Lan, N. C. (1997). Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593. Psychopharmacology 134, 46–54.
- 675 Weaver, C. E., Jr., Marek, P., Park-Chung, M., Tam, S. W., and Farb, D. H. (1997). Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-d-aspartate receptor. Proc. Nat. Acad. Sci. USA, 94, 10450–10454.
- 676 Sadri-Vakili, G., Johnson, D. W., Janis, G. C., Gibbs, T. T., Pierce, R. C., and Farb, D. H. (2003). Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate. J. Neurochem. 86, 92–101.
- 677 Moody, E. J., Suzdak, P. D., Paul, S. M., and Skolnick, P. (1988). Modulation of the benzodiazepine/γ-aminobutyric acid receptor chloride channel complex by inhalation anesthetics. J. Neurochem. 5, 1386–1393.
- 678 Zimmerman, S. A., Jones, M. V., and Harrison, N. L. (1994). Potentiation of γ-aminobutyric acidA receptor Cl− current correlates with in vivo anesthetic potency. J. Pharmacol. Exp. Ther. 270, 987–991.
- 679 Mihic, S. J., McQuilkin, S. J., Eger, E. I., Ionescu, P., and Harris, R. A. (1994). Potentiation of γ-aminobutyric acid type A receptor mediated chloride currents by novel halogenated compounds corresponds to their abilities to induce general anesthesia. Mol. Pharmacol. 46, 851–857.
- 680 Harrison, N. L., Kugler, J. L., Jones, M. V., Greenblatt, E. P., and Pritchett, D. B. (1993). Positive modulation of human γ-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane. Mol. Pharmacol. 44, 628–632.
- 681 Hall, A. C., Lieb, W. R., and Franks, N. P. (1994). Stereoselective and non-stereoselective actions of isoflurane on the GABAA receptor. Br. J. Pharmacol. 112, 906–910.
- 682 Harris, B. D., Wong, G., Moody, E. G., and Skolnick, P. (1995). Different subunit requirements for volatile and nonvolatile anesthetics at γ-aminobutyric acid type A receptors. Mol. Pharmacol. 47, 363–367.
- 683 Harris, R. A., Mihic, S. J., Dildy-Mayfield, J. E., and Machu, T. K. (1995). Actions of anesthetics on ligand-gated ion channels: Role of receptor subunit composition. FASEB J. 9, 1454–1462.
- 684 Lin, L. H., Chen, L. L., Zirrolli, J. A., and Harris, R. A. (1992). General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: Lack of involvement of intracellular calcium. J. Pharmacol. Exp. Ther. 263, 569–578.
- 685 Concas, A., Santoro, G., Mascia, M. P., Serra, M., Sanna, E., and Biggio, G. (1990). The general anesthetic propofol enhances the function of γ-aminobutyric acid-coupled chloride channel in the rat cerebral cortex. J. Neurochem. 55, 2135–2138.
- 686 Hara, M., Yoshihisa, K., and Ikemoto, Y. (1994). Enhancement by propofol of the γ-aminobutyric acid A response in dissociated hippocampal pyramidal neurons of the rat. Anesthesiology 81, 988–994.
- 687 Sanna, E., Murgia, A., Casula, A., Usala, M., Maciocco, E., Tuligi, G., and Biggio, G. (1996). Direct activation of GABAA receptors by loreclezole, an anticonvulsant drug with selectivity for the beta-subunit. Neuropharmacology 35, 1753–1760.
- 688 Akk, G., and Steinbach, J. H. (2000). Activation and block of recombinant GABAA receptors by pentobarbitone: A single-channel study. Br. J. Pharmacol. 130, 249–258.
- 689 Li, X., Czajkowski, C., and Pearce, R. A. (2000). Rapid and direct modulation of GABAA receptors by halothane. Anesthesiology 92, 1366–1375.
- 690 Mozrzymas, J. W., Barberis, A., Michalak, K., and Cherubini, E. (1999). Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors. J. Neurosci. 19, 2474–2488.
- 691 Li, X., and Pearce, R. A. (2000). Effects of halothane on GABAA receptor kinetics: Evidence for slowed agonist unbinding. J. Neurosci. 20, 899–907.
- 692 Bai, D., Pennefather, P. S., MacDonald, J. F., and Orser, B. A. (1999). The general anesthetic propofol slows deactivation and desensitization of GABAA receptors. J. Neurosci. 19, 10635–10646.
- 693 Wei, W., Faria, L. C., and Mody, I. (2004). Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J. Neurosci. 24, 8379–8382.
- 694Narahashi, T., Arakawa, O., Brunner, E. A., Nakahiro, M., Nishio, M., Ogata, N., Quandt, F. N., Tanguy, J., and Yeh, J. Z. (1992). GABAergic Synaptic Transmission. ( G. Biggio, A. Concas A., and E. Costa, eds.) Raven, New York, pp. 325–334.
- 695 Boissier, J. R., Simon, P., Zaczinska, M., and Fichelle, J. (1972). Etude experimentale d'une nouvelle substance psychotrope, la ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1 benzoxazine. Therapie 27, 325–338.
- 696 Patel, J. B., Malick, J. B., Salama, A. I., and Goldberg, M. E. (1985). Pharmacology of pyrazolopyridines. Pharmacol. Biochem. Behav. 23, 675–680.
- 697 Verleye, M., Schlichter, R., and Gillardin, J. M. (1999). Interaction of etifoxine with the chloride channel coupled to the GABAA receptor complex. Neuroreport 10, 3207–3210.
- 698 Verleye, M., Schlichter, R., Neliat, G., Pansart, Y., and Gillardin, J. M. (2001). Functional modulation of gamma-amino acid A receptor by etifoxine and allopregnanolone in rodents. Neurosci. Lett. 301, 191–194.
- 699 Verleye, M., Pansart, Y., and Gillardin, J. M. (2002). Effects of etifoxine on ligand binding to GABAA receptors in rodents. Neurosci. Res. 44, 167–172.
- 700 Schlichter, R., Rybalchenko, V., Poisbeau, P., Verleye, M., and Gillardin, J. M. (2000). Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology 39, 1523–1535.
- 701 Jenkins, A., Greenblatt, E. P., Faulkner, H. J., Bertaccini, E., Light, A., Lin, A., Andreasen, A., Viner, A., Trudell, J. R., and Harrison, N. L. (2001). Evidence for a common binding cavity for three general anesthetics within the GABAA receptor. J. Neurosci. 21, RC136.
- 702 Jackel, C., Kleinz, R., Makela, R., Hevers, W., Jezequel, S., Korpi, E. R., and Luddens, H. (1998). The main determinant of furosemide inhibition on GABAA receptors is located close to the first transmembrane domain. Eur. J. Pharmacol. 357, 251–256.
- 703 Krasowski, M. D., and Harrison, N. L. (2000). The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations. Br. J. Pharmacol. 129, 731–443.
- 704 Ernst, M., Bruckner, S., Boresch, S., and Sieghart, W. (2005). Comparative models of GABAA receptor extracellular and transmembrane domains: Important insights in pharmacology and function. Mol. Pharmacol. 68, 1291–1300.
- 705 Mihic, S. J., Ye, Q., Wick, M. J., Koltchine, V. V., Krasowski, M. D., Finn, S. E., Mascia, M. P., Valenzuela, C. F., Hanson, K. K., Greenblatt, E. P., Harris, R. A., and Harrison, N. L. (1997). Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389, 385–389.
- 706 Krasowski, M. D., O'Shea, S. M., Rick, C. E., Whiting, P. J., Hadingham, K. L., Czajkowski, C., and Harrison, N. L. (1997). Alpha subunit isoform influences GABAA receptor modulation by propofol. Neuropharmacology 36, 941–949.
- 707 Koltchine, V. V., Finn, S. E., Jenkins, A., Nikolaeva, N., Lin, A., and Harrison, N. L. (2001). Agonist gating and isoflurane potentiation in the human gamma-aminobutyric acid type A receptor determined by the volume of a second transmembrane domain residue. Mol. Pharmacol. 56, 1087–1093.
- 708 Jenkins, A., Andreasen, A., Trudell, J. R., and Harrison, N. L. (2002). Tryptophan scanning mutagenesis in TM4 of the GABAA receptor α1 subunit: Implications for modulation by inhaled anesthetics and ion channel structure. Neuropharmacology 43, 669–678.
- 709 Nishikawa, K., Jenkins, A., Paraskevakis, I., and Harrison, N. L. (2002). Volatile anesthetic actions on the GABAA receptors: Contrasting effects of α1S270 and β2N265 point mutations. Neuropharmacology 42, 337–345.
- 710 Nishikawa, K., and Harrison, N. L. (2003). The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: Effects of TM2 mutations in the alpha and beta subunits. Anesthesiology 99, 678–684.
- 711 Carlson, B. X., Engblom, A. C., Kristiansen, U., Schousboe, A., and Olsen, R. W. (2000). A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor β2 subunit affects allosteric sensitivity to GABA and anesthetics. Mol. Pharmacol. 57, 474–484.
- 712 Serafini, R., Bracamontes, J., and Steinbach, J. H. (2000). Structural domains of the human GABAA receptor β3 subunit involved in the actions of pentobarbital. J. Physiol. 524, 649–676.
- 713 Chang, C. S., Olcese, R., and Olsen, R. W. (2003). A single M1 residue in the β2 subunit alters channel gating of GABAA receptor in anesthetic modulation and direct activation. J. Biol. Chem. 278, 42821–42828.
- 714 Wingrove, P. B., Wafford, K. A., Bain, C., and Whiting, P. J. (1994). The modulatory action of loreclezole at the γ-aminobutyric acid type A receptor is determined by a single amino acid in the β2 and β3 subunit. Proc. Nat. Acad. Sci. USA, 91, 4569–4573.
- 715 Wooltorton, J. R., McDonald, B. J., Moss, S. J., and Smart, T. G. (1997). Identification of a Zn2+ binding site on the murine GABAA receptor complex: Dependence on the second transmembrane domain of β subunits. J. Physiol. 505, 633–640.
- 716 Horenstein, J., and Akabas, M. H. (1998). Location of a high affinity Zn2+ binding site in the channel of α1β1 γ-aminobutyric acidA receptors. Mol. Pharmacol. 53, 870–877.
- 717 Hosie, A. M., Dunne, E. L., Harvey, R. J., and Smart, T. G. (2003). Zinc-mediated inhibition of GABAA receptors: Discrete binding sites underlie subtype specificity. Nat. Neurosci. 6, 362–369.
- 718 Morris, K. D., and Amin, J. (2004). Insight into the mechanism of action of neuroactive steroids. Mol. Pharmacol. 66, 56–69.
- 719 Ueno, S., Tsutsui, M., Toyohira, Y., and Yanagiharaa, N. (2004). Sites of positive allosteric modulation by neurosteroids on ionotropic γ-aminobutyric acid receptor subunits. FEBS Lett. 566, 213–217.
- 720 Dillon, G. H., Im, H. K., Hamilton, B. J., Carter, D. B., Gammill, R. B., Judge, T. M., and Im, W. B. (1993). U-93631 causes rapid decay of gamma-aminobutyric acid-induced chloride currents in recombinant rat gamma-aminobutyric acid type A receptors. Mol. Pharmacol. 44, 860–865.
- 721 Nagata, K., Hamilton, B. J., Carter, D. B., and Narahashi, T. (1994). Selective effects of dieldrin on the GABAA receptor-channel subunits expressed in human embryonic kidney cells. Brain Res. 645, 19–26.
- 722 Nagata, K., and Narahashi, T. (1994). Dual action of the cyclodien insecticide dieldrin on the γ-aminobutyric acid receptor-chloride channel complex of rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 269, 164–171.
- 723 Bell-Horner, C. L., Dibas, M., Huang, R. Q., Drewe, J. A., and Dillon, G. H. (2000). Influence of subunit configuration on the interaction of picrotoxin-site ligands with recombinant GABAA receptors. Mol. Brain Res. 76, 47–55.
- 724 Huang, R. Q., Bell-Horner, C. L., Dibas, M. I., Covey, D. F., Drewe, J. A., and Dillon, G. H. (2001). Pentylenetetrazole-induced inhibition of recombinant gamma-aminobutyric acid type A receptors: Mechanism and site of action. J. Pharmacol. Exp. Ther. 298, 986–995.
- 725 Xu, M., Covey, D. F., and Akabas, M. H. (1995). Interaction of picrotoxin with GABAA receptor channel-lining residues probed in cysteine mutants. Biophys. J. 69, 1858–1867.
- 726 Perret, P., Sarda, X., Wolff, M., Wu, T. T., Bushey, D., and Goeldner, M. (1999). Interaction of non-competitive blockers within the gamma-aminobutyric acid type A chloride channel using chemically reactive probes as chemical sensors for cysteine mutants. J. Biol. Chem. 274, 25350–25354.
- 727 Dibas, M. I., and Dillon, G. H. (2000). The central nervous system convulsant pentylenetetrazole stimulates gamma-aminobutyric acid GABA-activated current in picrotoxin-resistant GABAA receptors in HEK293 cells. Neurosci. Lett. 285, 193–196.
- 728 Klunk, W. E., McKeon, A., Covey, D. F., and Ferrendelli, J. A. (1982). α-Substituted γ-butyrolactones: New class of anticonvulsant drugs. Science 217, 1040–1042.
- 729 Mathews, G. C., Bolos-Sy, A. M., Covey, D. F., and Rothman, S. M., and Ferrendelli, J. A. (1996). Physiological comparison of α-ethyl-α-methyl-γ-thiobutyrolactone with benzodiazepine and barbiturate modulators of GABAA receptors. Neuropharmacology 35, 123–136.
- 730 Holland, K. D., Yoon, K. W., Ferrendelli, J. A., Covey, D. F., and Rothman, S. M. (1991). γ-Butyrolactone antagonism of the picrotoxin receptor: Comparison of a pure antagonist and a mixed antagonist/inverse agonist. Mol. Pharmacol. 39, 79–84.
- 731 Holland, K. D., McKeon, A. C., Covey, D. F., and Ferrendelli, J. A. (1990). Binding interactions of convulsant and anticonvulsant γ-butyrolactones and γ-thiobutyrolactones with the picrotoxin receptor. J. Pharmacol. Exp. Ther. 254, 578–583.
- 732 Holland, K. D., Ferrendelli, J. A., Covey, D. F., and Rothman, S. M. (1990). Physiological regulation of the picrotoxin receptor by γ-butyrolactones and γ-thiobutyrolactones in cultured hippocampal neurons. J. Neurosci. 10, 1719–1727.
- 733 Holland, K. D., Bouley, M. G., Covey, D. F., and Ferrendelli, J. A. (1993). Alkylsubstituted γ-butyrolactones act at a distinct site allosterically linked to the TBPS/picrotoxinin site on the GABAA receptor complex. Brain Res. 615, 170–174.
- 734 Holland, K. D., Mathews, G. C., Bolos-Sy, A. M., Tucker, J. B., Reddy, P. A., Covey, D. F., Ferrendelli, J. A., and Rothman, S. M. (1995). Dual modulation of the γ-aminobutyric acid type A receptor/ionophore by alkyl-substituted γ-butyrolactones. Mol. Pharmacol. 47, 1217–1223.
- 735 Williams, K. L., Tucker, J. B., White, G., Weiss, D. S., Ferrendelli, J. A., Covey, D. F., Krause, J. E., and Rothman, S. M. (1997). Lactone modulation of the gamma-aminobutyric acid A receptor: Evidence for a positive modulatory site. Mol. Pharmacol. 52, 114–119.
- 736 Schwartz, R. D., Skolnick, P., and Paul, S. M. (1988). Regulation of gamma-aminobutyric acid/barbiturate receptor-gated chloride ion flux in brain vesicles by phospholipase A2: Possible role of oxygen radicals. J. Neurochem. 50, 565–571.
- 737 Schwartz, R. D., and Yu, X. (1992). Inhibition of GABA-gated chloride channel function by arachidonic acid. Brain Res. 585, 405–410.
- 738 Saxena, N. C. (2000). Inhibition of GABAA receptor currents by arachidonic acid in HEK 293 cells stably transfected with α1β2γ2 subunits. Pflugers Arch. 440, 380–392.
- 739 Chapell, R., Martin, J., Machu, T. K., and Leidenheimer, N. J. (1998). Direct channel-gating and modulatory effects of triiodothyronine on recombinant GABAA receptors. Eur. J. Pharmacol. 349, 115–121.
- 740 Pong, S. S., and Wang, C. C. (1982). Avermectin B modulation of γ-aminobutyric acid receptors in rat brain membranes. J. Neurochem. 38, 375–379.
- 741 Krusek, J., and Zemkova, H. (1994). Effect of ivermectin on γ-aminobutyric acid-induced chloride currents in mouse hippocampal embryonic neurones. Eur. J. Pharmacol. 259, 121–128.
- 742 Moody, E. J., and Skolnick, P. (1989). Chlormethiozole: Neurochemical actions at the γ-aminobutyric acid receptor complex. Eur. J. Pharmacol. 164, 153–158.
- 743 Hales, T. G., and Lambert, J. J. (1992). Modulation of GABAA and glycine receptors by chlormethiozole. Eur. J. Pharmacol. 210, 239–246.
- 744 Peoples, R. W., and Weight, F. F. (1994). Trichloroethanol potentiation of γ-aminobutyric acid-activated chloride current in mouse hippocampal neurones. Br. J. Pharmacol. 113, 555–563.
- 745 Gilad, G. M., Gilad, V. H., and Wyatt, R. J. (1992). Polyamines modulate the binding of GABAA-benzodiazepine receptor ligands in membranes from the rat forebrain. Neuropharmacology 31, 895–898.
- 746 Squires, R. F., and Saederup, E. (1988). Antidepressants and metabolites that block GABAA receptors coupled to [35S] t-butylbicyclophosphorothionate binding sites in rat brain. Brain Res. 441, 15–22.
- 747 Sander, C., and Schneider, R. (1991). Database of homology-derived structural meaning of sequence alignment. Proteins 9, 56–68.
- 748 Engblom, A. C., Carlson, B. X., Olsen, R. W., Schousboe, A., and Kristiansen, U. (2002). Point mutation in the first transmembrane region of the beta 2 subunit of the gamma-aminobutyric acid type A receptor alters desensitization kinetics of gamma-aminobutyric acid and anesthetic-induced channel gating. J. Biol. Chem. 277, 17438–17447.
- 749 Jones-Davis, D. M., Song, L., Gallagher, M. J., and Macdonald, R. L. (2005). Structural determinants of benzodiazepine allosteric regulation of GABAA receptor currents. J. Neurosci. 25, 8056–8065.
- 750 Rogers, C. J., Twyman, R. E., and Macdonald, R. (1994). Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture. J. Physiol. 475, 69–82.
- 751 Lavoie, A. M., and Twyman, R. E. (1996). Direct evidence for diazepam modulation of GABAA receptor microscopic affinity. Neuropharmacology 35, 1383–1392.
- 752 Boileau, A. J., Kucken, A. M., Evers, A. R., and Czajkowski, C. (1998). Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric-γ-aminobutyric acid A receptor subunits. Mol. Pharmacol. 53, 295–303.
- 753 Walters, R. J., Hadley, S. H., Morris, K. D. W., and Amin, J. (2000). Benzodiazepines act upon GABAA receptors via two distinct and separable mechanisms. Nat. Neurosci. 3, 1274–1281.
- 754 Dunn, S. M., Davies, M., Muntoni, A. L., and Lambert, J. J. (1999). Mutagenesis of the rat α1 subunit of the gamma-aminobutyric acidA receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands. Mol. Pharmacol. 56, 768–774.
- 755 Benson, J. A., Low, K., Keist, R., Mohler, H., and Rudolph, U. (1998). Pharmacology of recombinant γ-aminobutyric acid A receptors rendered diazepam-insensitive by point-mutated receptors. FEBS Lett. 431, 400–404.
- 756 Im, W. B., Pregenzer, J. F., Binder, J. A., Alberts, G. L., and Im, H. K. (1997). Alterations of the benzodiazepine site of rat α6β2γ2 GABAA receptor by replacement of several divergent amino-terminal regions with the α1 counterparts. Br. J. Pharmacol. 120, 559–564.
- 757 Berezhnoy, D., Nyfeler, Y., Gonthier, A., Schwob, H., Goeldner, M., and Sigel, E. (2004). On the benzodiazepine binding pocket in GABAA receptors. J. Biol. Chem. 279, 3160–3168.
- 758 Stevenson, A., Wingrove, P. B., Whiting, P. J., and Wafford, K. A. (1995). β-Carboline gamma-aminobutyric acidA receptor inverse agonists modulate gamma-aminobutyric acid via the loreclezole binding site as well as the benzodiazepine site. Mol. Pharmacol. 48, 965–969.
- 759 Im, H. K., Im, W. B., Pregenzer, J. F., Stratman, N. C., VonVoigtlander, P. F., and Jacobsen, E. J. (1998). Two imidazoquinoxaline ligands for the benzodiazepine site sharing a second low affinity site on rat GABAA receptors but with the opposite functionality. Br. J. Pharmacol. 123, 1490–1494.
- 760 Buhr, A., Baur, R., Malherbe, P., and Sigel, E. (1996). Point mutations of the α1β2γ2 γ-aminobutyric acidA receptor affecting modulation of the channel by ligands of the benzodiazepine binding site. Mol. Pharmacol. 49, 1080–1084.
- 761 Downing, S. S., Lee, Y. T., Farb, D. H., and Gibbs, T. T. (2005). Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation. Br. J. Pharmacol. 145, 894–906.
- 762Kostakis, E. E., Gravielle, M. C., Skolnick, P., Lippa, A. S., Russek, S. J., Gibbs, T. T., and Farb, D. H. (2003). Subtype selective modulation of GABAA receptor by Ocinaplon, an anxioselective pyrazolopyrimidine. Abstract presented at the Thirty-Third Annual Meeting of the Society for Neuroscience, New Orleans, Louisiana.
