Expression of the regulated isoform of the electrogenic Na/HCO cotransporter, NBCe1, is enriched in pacemaker interstitial cells of Cajal.

Interstitial cells of Cajal (ICCs) generate electrical slow waves, which are required for normal gastrointestinal motility. The mechanisms for generation of normal pacemaking are not fully understood. Normal gastrointestinal contractility and electrical slow-wave activity depend on the presence of extracellular HCO. Previous transcriptional analysis identified enrichment of mRNA encoding the electrogenic Na/HCO cotransporter (NBCe1) gene () in pacemaker myenteric ICCs in mouse small intestine. We aimed to determine the distribution of NBCe1 protein in ICCs of the mouse gastrointestinal tract and to identify the transcripts of the gene in mouse and human small intestinal tunica muscularis. We determined the distribution of NBCe1 immunoreactivity (NBCe1-IR) by immunofluorescent labeling in mouse and human tissues. In mice, NBCe1-IR was restricted to Kit-positive myenteric ICCs of the stomach and small intestine and submuscular ICCs of the large intestine, that is, the slow wave generating subset of ICCs. Other subtypes of ICCs were NBCe1-negative. Quantitative real-time PCR identified >500-fold enrichment of and transcripts ["IP3-receptor-binding protein released by IP3" (IRBIT)-regulated isoforms] in Kit-expressing cells isolated from Kit, Rpl22 mice and from single GFP-positive ICCs from Kit mice. Human jejunal tunica muscularis ICCs were also NBCe1-positive, and and RNAs were >300-fold enriched relative to . In summary, NBCe1 protein expressed in ICCs with electrical pacemaker function is encoded by gene transcripts that generate IRBIT-regulated isoforms of NBCe1. In conclusion, Na/HCO cotransport through NBCe1 contributes to the generation of pacemaker activity in subsets of ICCs. In this study, we show that the electrogenic Na+/HCO cotransporter, NBCe1/Slc4a4, is expressed in subtypes of interstitial cells of Cajal (ICCs) responsible for electrical slow wave generation throughout the mouse gastrointestinal tract and is absent in other types of ICCs. The transcripts of expressed in mouse ICCs and human gastrointestinal smooth muscle are the regulated isoforms. This indicates a key role for HCO transport in generation of gastrointestinal motility patterns.