Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine

Intestinal epithelial electrolyte secretion is activated by increase in intracellular cAMP or Ca and opening of apical Cl channels. In infants and young animals, but not in adults, Ca-activated chloride channels may cause secretory diarrhea during rotavirus infection. While detailed knowledge exists concerning the contribution of cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) channels, analysis of the role of Ca-dependent Cl channels became possible through identification of the anoctamin (TMEM16) family of proteins. We demonstrate expression of several anoctamin paralogues in mouse small and large intestines. Using intestinal-specific mouse knockout models for anoctamin 1 (Ano1) and anoctamin 10 (Ano10) and a conventional knockout model for anoctamin 6 (Ano6), we demonstrate the role of anoctamins for Ca-dependent Cl secretion induced by the muscarinic agonist carbachol (CCH). Ano1 is preferentially expressed in the ileum and large intestine, where it supports Ca-activated Cl secretion. In contrast, Ano10 is essential for Ca-dependent Cl secretion in jejunum, where expression of Ano1 was not detected. Although broadly expressed, Ano6 has no role in intestinal cholinergic Cl secretion. Ano1 is located in a basolateral compartment/membrane rather than in the apical membrane, where it supports CCH-induced Ca increase, while the essential and possibly only apical Cl channel is CFTR. These results define a new role of Ano1 for intestinal Ca-dependent Cl secretion and demonstrate for the first time a contribution of Ano10 to intestinal transport.