Expression of the regulated isoform of the electrogenic Na /HCO3 -cotransporter, NBCe1, is enriched in pacemaker interstitial cells of Cajal

Maria Gabriela Colmenares Aguilar, Amelia Mazzone, Seth T. Eisenman, Peter R. Strege, Cheryl E. Bernard, Heather L. Holmes, Michael F. Romero, Gianrico Farrugia, Simon J. Gibbons

Research output: Contribution to journalArticlepeer-review

Abstract

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 slowwave activity depend on the presence of extracellular HCO3 -. Previous transcriptional analysis identified enrichment of mRNA encoding the electrogenic Na /HCO3 - cotransporter (NBCe1) gene (Slc4a4) 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 Slc4a4 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 Kitpositive 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 Slc4a4-207 and Slc4a4-208 transcripts ["IP3-receptor-binding protein released by IP3" (IRBIT)-regulated isoforms] in Kitexpressing cells isolated from KitcreERT2/ , Rpl22tm1.1Psam/Sj mice and from single GFP-positive ICCs from Kittm1Rosay mice. Human jejunal tunica muscularis ICCs were also NBCe1-positive, and SLC4A4-201 and SLC4A4-204 RNAs were >300-fold enriched relative to SLC4A4-202. In summary, NBCe1 protein expressed in ICCs with electrical pacemaker function is encoded by Slc4a4 gene transcripts that generate IRBIT-regulated isoforms of NBCe1. In conclusion, Na /HCO3 - cotransport through NBCe1 contributes to the generation of pacemaker activity in subsets of ICCs.

Original languageEnglish (US)
Pages (from-to)G93-G107
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume320
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • "IP3-receptor binding protein released by IP3" (IRBIT)-regulated NBCe1-B/C
  • Bicarbonate transport in gastrointestinal motility
  • Human small intestine
  • Ribotag mouse
  • Slc4a4

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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