Quantitative Life Sciences PhD Program, McGill University, Montreal, Quebec, Canada.
Department of Physiology, McGill University, Montreal, Quebec, Canada.
J Gen Physiol. 2022 Jul 4;154(7). doi: 10.1085/jgp.202112921. Epub 2022 May 25.
Voltage-gated sodium (Nav) channels produce the upstroke of action potentials in excitable tissues throughout the body. The gating of these channels is determined by the asynchronous movements of four voltage-sensing domains (VSDs). Past studies on the skeletal muscle Nav1.4 channel have indicated that VSD-I, -II, and -III are sufficient for pore opening, whereas VSD-IV movement is sufficient for channel inactivation. Here, we studied the cardiac sodium channel, Nav1.5, using charge-neutralizing mutations and voltage-clamp fluorometry. Our results reveal that both VSD-III and -IV are necessary for Nav1.5 inactivation, and that steady-state inactivation can be modulated by all VSDs. We also demonstrate that channel activation is partially determined by VSD-IV movement. Kinetic modeling suggests that these observations can be explained from the cardiac channel's propensity to enter closed-state inactivation (CSI), which is significantly higher than that of other Nav channels. We show that skeletal muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.6 all have different propensities for CSI and postulate that these differences produce isoform-dependent roles for the four VSDs.
电压门控钠离子（Nav）通道在全身的可兴奋组织中产生动作电位的上升。这些通道的门控由四个电压感应结构域（VSD）的异步运动决定。过去对骨骼肌 Nav1.4 通道的研究表明，VSD-I、-II 和 -III 足以打开孔道，而 VSD-IV 的运动足以使通道失活。在这里，我们使用电荷中和突变和电压钳荧光法研究了心脏钠离子通道 Nav1.5。我们的结果表明，VSD-III 和 -IV 对于 Nav1.5 的失活都是必需的，并且稳态失活可以被所有 VSD 调节。我们还证明，通道激活部分由 VSD-IV 的运动决定。动力学建模表明，这些观察结果可以从心脏通道进入关闭状态失活（CSI）的倾向来解释，这种倾向明显高于其他 Nav 通道。我们表明，骨骼肌 Nav1.4、心脏 Nav1.5 和神经元 Nav1.6 都具有不同的 CSI 倾向，并假设这些差异产生了四个 VSD 的依赖于同工型的作用。
