Epithelial Chloride Transport by CFTR Requires TMEM16A

Overview

Journal Sci Rep

Specialty Science

Date 2017 Oct 1

PMID 28963502

Citations 76

Authors

Roberta Benedetto

Jiraporn Ousingsawat

Podchanart Wanitchakool

Yong Zhang

Michael J Holtzman

Margarida Amaral

Jason R Rock

Rainer Schreiber

Karl Kunzelmann

Affiliations

Soon will be listed here.

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 Ca 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 Ca-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 Ca store release, possibly engaging Store Operated cAMP Signaling (SOcAMPS) and activating Ca 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 Ca-dependent chloride transport.

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