Calcium-Activated Cl- Channel: Insights on the Molecular Identity in Epithelial Tissues.

Trey Rottgen,Andrew Nickerson,Vazhaikkurichi Rajendran

doi:10.3390/ijms19051432

Trey Rottgen, Andrew Nickerson + Show 1 more

Open Access

https://doi.org/10.3390/ijms19051432

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Abstract

Calcium-activated chloride secretion in epithelial tissues has been described for many years. However, the molecular identity of the channel responsible for the Ca2+-activated Cl− secretion in epithelial tissues has remained a mystery. More recently, TMEM16A has been identified as a new putative Ca2+-activated Cl− channel (CaCC). The primary goal of this article will be to review the characterization of TMEM16A, as it relates to the physical structure of the channel, as well as important residues that confer voltage and Ca2+-sensitivity of the channel. This review will also discuss the role of TMEM16A in epithelial physiology and potential associated-pathophysiology. This will include discussion of developed knockout models that have provided much needed insight on the functional localization of TMEM16A in several epithelial tissues. Finally, this review will examine the implications of the identification of TMEM16A as it pertains to potential novel therapies in several pathologies.

Highlights

Cellular Cl− ion movement is involved in a vast array of physiological processes [1,2,3,4,5]
Cells isolated from a pancreatic tumor arising in a Cystic Fibrosis (CF) patient demonstrated a similar profile of Cl− secretion to that of the respiratory epithelium (52)
As far as pathology related to TMEM16A in colonic epithelium, less is known partially due to an incomplete knowledge as to the expression of the channel in human colon

Summary

Introduction

Cellular Cl− ion movement is involved in a vast array of physiological processes [1,2,3,4,5]. Cells isolated from a pancreatic tumor arising in a CF patient demonstrated a similar profile of Cl− secretion to that of the respiratory epithelium (52) This led to the understanding that the observed Ca2+-activated Cl− secretion was serving a compensatory role in the absence of the cAMP-stimulated Cl− secretion [8,10]. Yang et al demonstrated a slight-voltage dependence of TMEM16A at submicromolar and low micromolar concentrations of Ca2+, which was similar to the native protein [21] This effect was illustrated by greater channel activation at more depolarized potentials (+60 mV vs −60 mV) in transfected human embryonic kidney 293 (HEK 293) cells with varying Ca2+ concentrations [21]. This study further established the possibility of this specific CaCC being ubiquitous, and the long sought-after native CaCC [19]

TMEM16A Characterization

TMEM16A in Epithelial Tissues

Respiratory Epithelium

Colonic Epithelium

Conclusions