Bicarbonate ion transport by the electrogenic Na+ /HCO3- cotransporter, NBCe1, is required for normal electrical slow-wave activity in mouse small intestine

Wenchang Zhao; Liwen Zhang; Leonid G Ermilov; Maria Gabriela Colmenares Aguilar; David R Linden; Seth T Eisenman; Michael F Romero; Gianrico Farrugia; Lei Sha; Simon J Gibbons

doi:10.1111/nmo.14149

Bicarbonate ion transport by the electrogenic Na⁺ /HCO₃^- cotransporter, NBCe1, is required for normal electrical slow-wave activity in mouse small intestine

Neurogastroenterol Motil. 2021 Sep;33(9):e14149. doi: 10.1111/nmo.14149. Epub 2021 Apr 10.

Authors

Wenchang Zhao^{1

2

3}, Liwen Zhang^{1

2

3}, Leonid G Ermilov^{1

2}, Maria Gabriela Colmenares Aguilar^{1

2}, David R Linden^{1

2}, Seth T Eisenman^{1

2}, Michael F Romero^{2

4}, Gianrico Farrugia^{1

2}, Lei Sha³, Simon J Gibbons^{1

2}

Affiliations

¹ Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Rochester, MN, USA.
² Physiology and Biomedical Engineering, Rochester, MN, USA.
³ Neuroendocrine Pharmacology, China Medical University, Shenyang, China.
⁴ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

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.

Keywords: Slc4a4 protein; biological pacemakers; gastrointestinal motility; interstitial cells of Cajal; mouse; small intestine; smooth muscle.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bicarbonates / metabolism*
Female
Gastrointestinal Motility / physiology*
Intestine, Small / physiology*
Ion Transport / physiology
Male
Mice
Mice, Inbred C57BL
Sodium-Bicarbonate Symporters / metabolism*

Substances

Bicarbonates
Sodium-Bicarbonate Symporters

Abstract

Publication types

MeSH terms

Substances

Grants and funding