1. Resting state structure of the hyperdepolarization activated two-pore channel 3.
- Author
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Dickinson, Miles Sasha, Myasnikov, Alexander, Eriksen, Jacob, Poweleit, Nicole, and Stroud, Robert M.
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VOLTAGE-gated ion channels , *ACTIVATION energy , *SODIUM channels , *CHEMICAL structure - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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