PDF(Pubmed)
Abstract：
Voltage-gated sodium channels (Naᵥ) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Naᵥ channels transition from the resting, closed state to an open, conductive state, before rapidly inactivating. Dysregulation of this functional cycle due to mutations causes diseases including epilepsy, pain conditions, and cardiac disorders, making Naᵥ channels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P2 decreases Naᵥ1.4 activity by increasing the difficulty of channel opening, accelerating fast inactivation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P2 binds stably to inactivated Naᵥ at a conserved site within the DIV S4-S5 linker, which couples the voltage-sensing domain (VSD) to the pore. As the Naᵥ C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesize that PI(4,5)P2 prolongs inactivation by competitively binding to this site. In atomistic simulations, PI(4,5)P2 reduces the mobility of both the DIV S4-S5 linker and the DIII-IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Naᵥ model, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Naᵥ-related diseases.
摘要：
电压门控钠通道（Na）是膜蛋白，可打开以促进钠离子向内流入可兴奋细胞。为了响应刺激，纳频道从休息过渡，关闭状态到打开状态，导电状态，在迅速失活之前。由于突变导致的这种功能循环失调会导致包括癫痫在内的疾病，疼痛状况,和心脏疾病，使Na通道成为重要的药理靶标。磷酸肌醇是离子通道功能的重要脂质辅因子。磷酸肌醇PI（4,5）P2通过增加通道开放的难度来降低NaZ1.4活性，加速快速失活和减缓从快速失活的恢复。使用多尺度分子动力学模拟，我们显示PI(4,5)P2在DIVS4-S5接头内的保守位点稳定地与灭活的Na结合，其将电压传感域(VSD)耦合到孔。由于NaC末端结构域被提议在从失活恢复期间也结合在这里，我们假设PI(4,5)P2通过竞争性结合该位点延长失活。在原子模拟中，PI（4,5）P2降低了DIVS4-S5接头和DIII-IV接头的迁移率，负责快速灭活，减缓通道恢复到静息状态所需的构象变化。我们进一步证明，在静息状态下，磷酸肌醇结合VSD门控电荷，这可能会锚定它们并阻碍VSD激活。我们的结果提供了一种机制，通过该机制，磷酸肌醇会改变激活的电压依赖性和从失活中恢复的速率，这是开发治疗钠相关疾病的新疗法的重要一步。
