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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere14149
JournalNeurogastroenterology and Motility
Issue number9
StatePublished - Sep 2021


  • Slc4a4 protein
  • biological pacemakers
  • gastrointestinal motility
  • interstitial cells of Cajal
  • mouse
  • small intestine
  • smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Endocrine and Autonomic Systems
  • Gastroenterology


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