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

• Published in: Neurogastroenterology and motility 2021-09, Vol.33 (9), p.e14149-n/a
• Main Authors: Zhao, Wenchang, Zhang, Liwen, Ermilov, Leonid G., Colmenares Aguilar, Maria Gabriela, Linden, David R., Eisenman, Seth T., Romero, Michael F., Farrugia, Gianrico, Sha, Lei, Gibbons, Simon J.
• Format: Article
• Language: English
• Subjects: Bicarbonates; biological pacemakers; Depolarization; Electrodes; Gastric motility; gastrointestinal motility; Gastrointestinal tract; Homeostasis; Immunohistochemistry; Interstitial cells; Interstitial cells of Cajal; mouse; Pacemakers; Slc4a4 protein; Small intestine; Smooth muscle; Transcription
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.14149

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. Model for the role of electrogenic Na+/HCO3− cotransport by NBCe1 in slow‐wave generation by Interstitial Cells of Cajal (ICC). Transport of extracellular HCO3− results in membrane potential (Em) hyperpolarization, and faster, more frequent slow waves probably by increasing intracellular pH and altering Ca2+ handling in ICC.