2. Academic Validation
  3. Epithelial Chloride Transport by CFTR Requires TMEM16A

Epithelial Chloride Transport by CFTR Requires TMEM16A

  • Sci Rep. 2017 Sep 29;7(1):12397. doi: 10.1038/s41598-017-10910-0.
Roberta Benedetto 1,  Jiraporn Ousingsawat 1,  Podchanart Wanitchakool 1,  Yong Zhang 2,  Michael J Holtzman 2,  Margarida Amaral 3,  Jason R Rock 4,  Rainer Schreiber 1,  Karl Kunzelmann 5
Affiliations

Affiliations

  • 1 Physiological institute, University of Regensburg, University street 31, D-93053, Regensburg, Germany.
  • 2 Department of Medicine and Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 3 University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, C8, 1749-016, Lisboa, Portugal.
  • 4 Department of Anatomy, University of California, San Francisco, USA.
  • 5 Physiological institute, University of Regensburg, University street 31, D-93053, Regensburg, Germany. [email protected].
PMID: 28963502 DOI: 10.1038/s41598-017-10910-0
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.

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