Voltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, β1-β4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel's voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of β-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel's propensity for closed-state inactivation, which in turn modulates the actions of β1 and β3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by β1 and β3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.

中文翻译：

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电压门控钠通道的固有门控行为预定由辅助β亚基调节

电压门控钠（Nav）通道在可激发细胞中介导快速毫秒级的电信号传递。辅助亚基β1-β4被认为通过与通道电压感应域的共价和/或极性相互作用来调节Nav通道功能。这些相互作用如何转化为β-亚基的多样且可变的调节作用尚不清楚。在这里，我们发现通道选通期间电压感应域的固有移动顺序在Nav通道同工型之间出乎意料地可变。该运动顺序决定了通道处于关闭状态灭活的倾向，这反过来又调节了β1和β3的作用。我们表明，骨骼肌，心脏和神经元Nav通道的差异调节是由其可变状态的关闭状态失活解释的。一起，