Modulation of cardiac ionic homeostasis by 3-iodothyronamine
Sandra Ghelardoni
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSilvia Suffredini
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorSabina Frascarelli
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSimona Brogioni
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorGrazia Chiellini
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSimonetta Ronca-Testoni
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorDavid K. Grandy
Departments of Physiology & Pharmacology and Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA
Search for more papers by this authorThomas S. Scanlan
Departments of Physiology & Pharmacology and Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA
Search for more papers by this authorElisabetta Cerbai
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorCorresponding Author
Riccardo Zucchi
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Correspondence to: R. ZUCCHI, M.D., Dip. di Scienze dell’Uomo e dell’Ambiente via Roma 55, 56126 Pisa, Italy.Tel.: +39-050-2218657Fax:+39-050-2218660E-mail: [email protected]Search for more papers by this authorSandra Ghelardoni
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSilvia Suffredini
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorSabina Frascarelli
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSimona Brogioni
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorGrazia Chiellini
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorSimonetta Ronca-Testoni
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Search for more papers by this authorDavid K. Grandy
Departments of Physiology & Pharmacology and Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA
Search for more papers by this authorThomas S. Scanlan
Departments of Physiology & Pharmacology and Cell & Developmental Biology, Oregon Health & Science University, Portland, OR, USA
Search for more papers by this authorElisabetta Cerbai
Dipartimento di Farmacologia, University of Florence, Florence, Italy
Search for more papers by this authorCorresponding Author
Riccardo Zucchi
Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy
Correspondence to: R. ZUCCHI, M.D., Dip. di Scienze dell’Uomo e dell’Ambiente via Roma 55, 56126 Pisa, Italy.Tel.: +39-050-2218657Fax:+39-050-2218660E-mail: [email protected]Search for more papers by this authorAbstract
3-iodothyronamine (T1AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20–25 μM T1AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 μM T1AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T1AM decreased transient outward current (Ito) and IK1 background current. SR studies involving 20 μM T1AM revealed a significant decrease in ryanodine binding due to reduced Bmax, no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T1AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of Ito and IK1 currents.
References
- 1 Scanlan TS, Suchland KL, Hart ME, et al . 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nature Med. 2004; 10: 638–42.
- 2 Chiellini G, Frascarelli S, Ghelardoni S, et al . Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function. FASEB J. 2007; 21: 1597–608.
- 3 Zucchi R, Chiellini G, Scanlan TS, et al . Trace amine-associated receptors and their ligands. Br J Pharmacol. 2006; 149: 967–78.
- 4 Grandy DK. Trace amine-associated receptor 1 – family archetype or iconoclast? Pharmacol & Ther. 2007; 116: 355–90.
- 5 Hart ME, Suchland KL, Miyakawa M, et al . Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. J Med Chem. 2006; 49: 1101–12.
- 6 Zucchi R, Limbruno U, Poddighe R, et al . Purine release from isolated rat heart: a new approach to the study of energy metabolism. J Mol Cell Cardiol. 1990; 22: 815–26.
- 7 Cerbai E, Barbieri M, Mugelli A. Characterization of the hyperpolarization-activated current, If, in ventricular myocytes isolated from hypertensive rats. J Physiol. 1994; 481: 585–91.
- 8 Sartiani L, Cerbai E, Lonardo G, et al . Prenatal exposure to carbon monoxide affects postnatal cellular electrophysiological maturation of the rat heart: a potential substrate for arrhythmogenesis in infancy. Circulation. 2004; 109: 419–23.
- 9 Zucchi R, Ronca-Testoni S, Yu G, et al . Effect of ischemia and reperfusion on cardiac ryanodine receptors – sarcoplasmic reticulum Ca2+ channels. Circ Res. 1994; 74: 271–80.
- 10 Zucchi R, Ronca-Testoni S, Yu G, et al . Postischemic changes in cardiac sarcoplasmic reticulum Ca2+ channels: A possible mechanism of ischemic preconditioning. Circ Res. 1995; 76: 1049–56.
- 11 Zucchi R, Gongyuan Y, Ghelardoni S, et al . Effect of MEN 10755, a new disaccharide analogue of doxorubicin, on sarcoplasmic reticulum Ca2+ handling and contractile function in rat heart. Br J Pharmacol. 2000; 131: 342–8.
- 12 Feher JJ, Lebolt WR, Manson NH. Differential effect of global ischemia on the ryanodine-sensiive and ryanodine-insensitive calcium uptake of cardiac sarcoplasmic reticulum. Circ Res. 1989; 65: 1400–8.
- 13 Chu A, Submilla C, Scales D, et al . Trypsin digestion of junctional sarcoplasmic reticulum vesicles. Biochemistry. 1998; 27: 2827–33.
- 14 Richard S, Charnet P, Nerbonne JM. Interconversion between distinct gating pathways of the high threshold calcium channel in rat ventricular myocytes. J Physiol. 1993; 462: 197–228.
- 15 Barrere-Lemaire S, Piot C, Leclercq F, et al . Facilitation of L-type calcium currents by depolarization in cardiac cells: impairment in heart failure. Cardiovasc Res. 2000; 47: 336–49.
- 16 Delgado C, Artiles A, Gómez AM, et al . Frequency-dependent increase in cardiac Ca2+ current is due to reduced Ca2+ release by the sarcoplasmic reticulum. J Mol Cell Cardiol. 1999; 31: 1783–93.
- 17 Zucchi R, Ronca-Testoni S. The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev. 1997; 49: 1–51.
- 18 Frascarelli S, Ghelardoni S, Chiellini G, et al . Cardiac effects of trace amines: pharmacological characterization of trace amine-associated receptors. Eur J Pharmacol. 2008; 587: 231–6.
- 19 Bers DM. Excitation-contraction coupling and cardiac contractile force. Dordrecht , The Netherlands : Kluwer; 2001.
- 20 Eisner DA, Trafford AW, Diaz ME, et al . The control of Ca release from the cardiac sarcoplasmic reticulum: regulation versus autoregulation. Cardiovasc Res. 1998; 38: 589–604.
- 21 Eisner DA, Choi HS, Diaz ME, et al . Integrative analysis od calcium cycling in cardiac muscle. Circ Res. 2000; 87: 1087–94.
- 22 Marx SO, Reiken S, Hisamatsu Y, et al . PKA phosphorylation dissociates FKPB12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000; 101: 365–76.
- 23 Lindemann L, Ebeling M, Kratochwil NA, et al . Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics. 2005; 85: 372–85.
- 24 Ogura T, Shuba LM, McDonald TF. L-type Ca2+ current in guinea pig ventricular myocytes treated with modulators of tyrosine phosphorylation. Am J Physiol. 1999; 276: H1724–33.
- 25 Wang WH, Lin DH, Sterling H. Regulation of ROMK channels by protein tyrosine kinase and tyrosine phosphatase. Trends Cardiovasc Med. 2000; 12: 138–42.
- 26 Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. Endocr Rev. 2005; 26: 704–28.
- 27 Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116: 1725–35.
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