Abstract
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the secretory chloride/bicarbonate channel in airways and intestine that is activated through ATP binding and phosphorylation by protein kinase A, but fails to operate in cystic fibrosis (CF). TMEM16A (also known as anoctamin 1, ANO1) is thought to function as the Ca2+ activated secretory chloride channel independent of CFTR. Here we report that tissue specific knockout of the TMEM16A gene in mouse intestine and airways not only eliminates Ca2+-activated Cl− currents, but unexpectedly also abrogates CFTR-mediated Cl− secretion and completely abolishes cAMP-activated whole cell currents. The data demonstrate fundamentally new roles of TMEM16A in differentiated epithelial cells: TMEM16A provides a mechanism for enhanced ER Ca2+ store release, possibly engaging Store Operated cAMP Signaling (SOcAMPS) and activating Ca2+ regulated adenylyl cyclases. TMEM16A is shown to be essential for proper activation and membrane expression of CFTR. This intimate regulatory relationship is the cause for the functional overlap of CFTR and Ca2+-dependent chloride transport.
Highlights
The cystic fibrosis transmembrane conductance regulator (CFTR) and the calcium-activated chloride channel TMEM16A are the two major secretory anion channels in intestinal and airway epithelia and provide the critical regulation of mucus hydration at these sites[1,2,3,4]
This decrease in transport function was not accompanied by any change in the level of CFTR expression in colonic epithelial cells based on TMEM16A western blotting (Fig. S1d)
The results show that calcium-activated as well as cAMP-stimulated CFTR-dependent chloride secretion in mouse intestinal epithelial cells depends on TMEM16A expression
Summary
The cystic fibrosis transmembrane conductance regulator (CFTR) and the calcium-activated chloride channel TMEM16A (anoctamin 1) are the two major secretory anion channels in intestinal and airway epithelia and provide the critical regulation of mucus hydration at these sites[1,2,3,4]. We generated mouse lines in which TMEM16A expression was selectively deleted in intestinal villus and crypt epithelial cells (using Vil1-Cre–TMEM16Aflox/flox mice) or ciliated airway epithelial cells (using FOXJ1-Cre– TMEM16Aflox/flox mice). This approach allowed for the first studies of adult mice with TMEM16A deficiency and demonstrated that TMEM16A expression is responsible for the calcium-activated chloride anion current in the intestine and lower respiratory airways and is essential for CFTR function at both of these mucosal sites
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