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Proc Natl Acad Sci U S A. 2020 Jan 28;117(4):1988-1993. doi: 10.1073/pnas.1915144117. Epub 2020 Jan 10.

Resting state structure of the hyperdepolarization activated two-pore channel 3.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
2
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA 94158.
3
Department of Neurology, University of California, San Francisco, CA 94158.
4
Department of Physiology, University of California, San Francisco, CA 94158.
5
Department of Medicine, University of California, San Francisco, CA 94158.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; stroud@msg.ucsf.edu.

Abstract

Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between -20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. The structure, confirmed by our electrophysiology, illustrates the configuration of a bona fide resting state voltage sensor, observed without the need for any inhibitory ligand, and independent of any chemical or mutagenic alteration.

KEYWORDS:

cryoEM; electrophysiology; ion channel; structure; voltage sensors

PMID:
31924746
PMCID:
PMC6995003
[Available on 2020-07-10]
DOI:
10.1073/pnas.1915144117

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