Electrophysiological changes in Slc26a3 (down‐regulated in adenoma, Dra) knockout intestine are associated with epithelial cell alkalinity

Abstract

Dra is the major apical membrane anion exchanger in the small and large intestine. Studies of recombinant DRA have proposed an electrogenic 2Cl−:1HCO3− stoichiometry (J. Gen. Physiol. 127: 511, 2006). However, in Dra knockout mice (DraKO) loss of Cl− absorption is associated with only small increases in transepithelial short‐circuit current (Isc). To investigate the electrophysiological changes resulting from loss of Dra, microelectrode analysis, intracellular pH (pHi) microfluorimetry and Ussing chamber studies were performed on DraKO and wild‐type (WT) intestine. Microelectrode studies revealed that the apical membrane potential (Va) of cecal epithelium was paradoxically greater in the DraKO and Va depolarization induced by extracellular Cl− (Cl−o) removal was not different than WT. Studies of cystic fibrosis mouse intestine indicated that Va depolarization during Cl−o removal was CFTR dependent and eliminated by high [K+]. Microfluorimetry studies revealed alkaline pHi in DraKO small and large intestinal epithelia. Ussing chamber experiments of DraKO small intestine found that increased Isc was abolished by epithelial acidification. We conclude that intestinal Dra demonstrates an electroneutral stoichiometry (e.g., 1Cl−:1HCO3−) and that increased Isc in DraKO intestine is associated with epithelial alkalinity that may activate basolateral membrane K+ channels. Support: NIDDK and CFF.