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.

中文翻译：

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超去极化激活的两孔通道3。

电压门控离子通道使膜具有兴奋性，并能传播形成所有神经元信号传导基础的动作电位。我们确定了电压门控钠通道，两孔通道3（TPC3）的结构，该通道可产生超长动作电位。与其他TPC和NaV通道在-20至0 mV之间激活的TPC3相比，TPC3仅在极端的膜去极化（V50〜+75 mV）时才被激活。我们提供的电生理证据表明，TPC3电压激活仅取决于电压感应域2（VSD2），并且VSD2中的三个门精氨酸均降低了激活阈值。该结构为钠的选择性提供了化学基础，狭窄的浇口表明封闭的孔与极端的电压依赖性一致。结构，