The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2018 Feb 27

PMID 29478917

Citations 50

Authors

Christian J Peters

John M Gilchrist

Jason Tien

Neville P Bethel

Lijun Qi

Tingxu Chen

Lynn Wang

Yuh Nung Jan

Michael Grabe

Lily Y Jan

Affiliations

Soon will be listed here.

Abstract

Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.

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