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

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

doi:10.1016/j.neuron.2018.01.048

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

Neuron. 2018 Mar 7;97(5):1063-1077.e4. doi: 10.1016/j.neuron.2018.01.048. Epub 2018 Feb 22.

Authors

Affiliations

¹ Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: christian.peters@ucsf.edu.
² Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lily.jan@ucsf.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Anoctamin-1 / chemistry*
Anoctamin-1 / genetics
Anoctamin-1 / metabolism*
Chloride Channels / chemistry*
Chloride Channels / genetics
Chloride Channels / metabolism*
HEK293 Cells
Humans
Ion Channel Gating / physiology*
Mice
Protein Binding / physiology
Protein Structure, Secondary

Substances

ANO1 protein, mouse
Anoctamin-1
Chloride Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding