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

Significance Voltage-gated ion channels (VGICs) initiate and transmit action potentials in nerve and muscle cells. Because they are generally activated by depolarization of the membrane potential, their structures usually represent activated channel states since they are necessarily determined in the absence of a voltage gradient. We determined the structure of a resting intact VGIC at 3.2 Å resolution by cryogenic electron microscopy. This structure provides the first resting state of a voltage sensor to be observed without the need for any inhibitory ligand, independent of any chemical, or mutagenic alteration. 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.