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

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.