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Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A


Lam, Andy K M; Dutzler, Raimund (2018). Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A. eLife, 7:39122.

Abstract

TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca. This channel comprises two independent pores and closely apposed Ca binding sites that are contained within each subunit of a homodimeric protein. Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino et al., 2017a). Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations. The currents of constitutively active mutants lose their outward rectification as a function of Ca concentration due to the alleviation of energy barriers for anion conduction. This phenomenon originates from Coulombic interactions between the bound Ca and permeating anions and thus demonstrates that an electrostatic gate imposed by the vacant binding site present in the sterically open pore, is released by Ca binding to enable an otherwise sub-conductive pore to conduct with full capacity.

Abstract

TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca. This channel comprises two independent pores and closely apposed Ca binding sites that are contained within each subunit of a homodimeric protein. Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino et al., 2017a). Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations. The currents of constitutively active mutants lose their outward rectification as a function of Ca concentration due to the alleviation of energy barriers for anion conduction. This phenomenon originates from Coulombic interactions between the bound Ca and permeating anions and thus demonstrates that an electrostatic gate imposed by the vacant binding site present in the sterically open pore, is released by Ca binding to enable an otherwise sub-conductive pore to conduct with full capacity.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > General Immunology and Microbiology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:English
Date:12 October 2018
Deposited On:07 Dec 2018 14:09
Last Modified:22 Jun 2020 20:09
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/eLife.39122
PubMed ID:30311910

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