Bicarbonate ion transport by the electrogenic Na+/HCO3− cotransporter, NBCe1, is required for normal electrical slow-wave activity in mouse small intestine
Wenchang Zhao
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Search for more papers by this authorLiwen Zhang
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Search for more papers by this authorLeonid G. Ermilov
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorMaria Gabriela Colmenares Aguilar
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorDavid R. Linden
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorSeth T. Eisenman
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorMichael F. Romero
Physiology and Biomedical Engineering, Rochester, MN, USA
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorGianrico Farrugia
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorCorresponding Author
Lei Sha
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Correspondence
Simon J. Gibbons, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Email: [email protected]
Lei Sha, China Medical University, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning Province 110122, China
Emails: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Simon J. Gibbons
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Correspondence
Simon J. Gibbons, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Email: [email protected]
Lei Sha, China Medical University, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning Province 110122, China
Emails: [email protected]; [email protected]
Search for more papers by this authorWenchang Zhao
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Search for more papers by this authorLiwen Zhang
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Search for more papers by this authorLeonid G. Ermilov
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorMaria Gabriela Colmenares Aguilar
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorDavid R. Linden
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorSeth T. Eisenman
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorMichael F. Romero
Physiology and Biomedical Engineering, Rochester, MN, USA
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorGianrico Farrugia
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Search for more papers by this authorCorresponding Author
Lei Sha
Neuroendocrine Pharmacology, China Medical University, Shenyang, China
Correspondence
Simon J. Gibbons, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Email: [email protected]
Lei Sha, China Medical University, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning Province 110122, China
Emails: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Simon J. Gibbons
Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA
Physiology and Biomedical Engineering, Rochester, MN, USA
Correspondence
Simon J. Gibbons, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Email: [email protected]
Lei Sha, China Medical University, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning Province 110122, China
Emails: [email protected]; [email protected]
Search for more papers by this authorWenchang Zhao and Liwen Zhang contributed equally to this work.
Funding information
This work was supported by NIH R01 DK57061 to Dr. Gibbons and Dr. Farrugia, by the Mayo Clinic Center for Cell Signaling in Gastroenterology P30DK084567, and Grant No. 81670492 from the National Natural Science Foundation of China to Dr. Lei Sha.
Abstract
Background
Normal gastrointestinal motility depends on electrical slow-wave activity generated by interstitial cells of Cajal (ICC) in the tunica muscularis of the gastrointestinal tract. A requirement for HCO3− in extracellular solutions used to record slow waves indicates a role for HCO3− transport in ICC pacemaking. The Slc4a4 gene transcript encoding the electrogenic Na+/HCO3− cotransporter, NBCe1, is enriched in mouse small intestinal myenteric region ICC (ICC-MY) that generate slow waves. This study aimed to determine how extracellular HCO3− concentrations affect electrical activity in mouse small intestine and to determine the contribution of NBCe1 activity to these effects.
Methods
Immunohistochemistry and sharp electrode electrical recordings were used.
Key Results
The NBCe1 immunoreactivity was localized to ICC-MY of the tunica muscularis. In sharp electrode electrical recordings, removal of HCO3- from extracellular solutions caused significant, reversible, depolarization of the smooth muscle and a reduction in slow-wave amplitude and frequency. In 100 mM HCO3−, the muscle hyperpolarized and slow wave amplitude and frequency increased. The effects of replacing extracellular Na+ with Li+, an ion that does not support NBCe1 activity, were similar to, but larger than, the effects of removing HCO3-. There were no additional changes to electrical activity when HCO3- was removed from Li+ containing solutions. The Na+/HCO3− cotransport inhibitor, S-0859 (30µM) significantly reduced the effect of removing HCO3− on electrical activity.
Conclusions & Inferences
These studies demonstrate a major role for Na+/HCO3− cotransport by NBCe1 in electrical activity of mouse small intestine and indicated that regulation of intracellular acid:base homeostasis contributes to generation of normal pacemaker activity in the gastrointestinal tract.
DISCLOSURES
None of the authors have any relevant disclosures to declare in respect of this work.
Supporting Information
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