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Resting state structure of the hyperdepolarization activated two-pore channel 3 [Biophysics and Computational Biology]
PNAS ( IF 9.580 ) Pub Date : 2020-01-10 , DOI: 10.1073/pnas.1915144117
Miles Sasha Dickinson, Alexander Myasnikov, Jacob Eriksen, Nicole Poweleit, Robert M. Stroud

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.
更新日期:2020-01-13

 

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