OHRI, Ottawa, ON, Canada.
Prog Biophys Mol Biol. 2012 Oct-Nov;110(2-3):245-56. doi: 10.1016/j.pbiomolbio.2012.07.003. Epub 2012 Jul 27.
The ceaseless opening and closing of the voltage-gated channels (VGCs) underlying cardiac rhythmicity is controlled, in each VGC, by four mobile voltage sensors embedded in bilayer. Every action potential necessitates extensive packing/repacking of voltage sensor domains with adjacent interacting lipid molecules. This renders VGC activity mechanosensitive (MS), i.e., energetically sensitive to the bilayer's mechanical state. Irreversible perturbations of sarcolemmal bilayer such as those associated with ischemia, reperfusion, inflammation, cortical-cytoskeleton abnormalities, bilayer-disrupting toxins, diet aberrations, etc, should therefore perturb VGC activity. Disordered/fluidized bilayer states that facilitate voltage sensor repacking, and thus make VGC opening too easy could, therefore, explain VGC-leakiness in these conditions. To study this in membrane patches we impose mechanical blebbing injury during pipette aspiration-induced membrane stretch, a process that modulates VGC activity irreversibly (plastic regime) and then, eventually, reversibly (elastic regime). Because of differences in sensor-to-gate coupling among different VGCs, their responses to stretch fall into two major categories, MS-Speed, MS-Number, exemplified by Nav and Cav channels. For particular VGCs in perturbed bilayers, leak mechanisms depend on whether or not the rate-limiting voltage-dependent step is MS. Mode-switch transitions might also be mechanosensitive and thus play a role. Incorporated mathematically in axon models, plastic-regime Nav responses elicit ectopic firing behaviors typical of peripheral neuropathies. In cardiomyocytes with mild bleb damage, Nav and/or Cav leaks from irreversible MS modulation (MS-Speed, MS-Number, respectively) could, similarly, foster ectopic arrhythmias. Where pathologically leaky VGCs reside in damaged bilayer, peri-channel bilayer disorder/fluidity conditions could be an important "target feature" for anti-arrhythmic VGC drugs.
心脏节律性的电压门控通道（VGC）的不断开启和关闭由嵌入双层的四个移动电压传感器控制。每个动作电位都需要大量的电压传感器结构域与相邻的相互作用脂质分子进行包装/重新包装。这使得 VGC 活动具有机械敏感性（MS），即对双层的机械状态敏感。因此，质膜双层的不可逆扰动，如与缺血、再灌注、炎症、皮质-细胞骨架异常、破坏双层的毒素、饮食失常等相关的扰动，应该会扰乱 VGC 活性。无序/流体化的双层状态有利于电压传感器的重新包装，从而使 VGC 更容易打开，因此可以解释这些条件下 VGC 渗漏的原因。为了在膜片钳实验中研究这一点，我们在管吸诱导的膜拉伸过程中施加机械泡状损伤，这个过程不可逆地调节 VGC 活性（塑性阶段），然后最终是可逆地调节（弹性阶段）。由于不同 VGC 之间的传感器到门控的耦合差异，它们对拉伸的反应分为两类，即 MS-Speed 和 MS-Number，以 Nav 和 Cav 通道为例。对于受扰动双层中的特定 VGC，渗漏机制取决于限速的电压依赖性步骤是否是 MS。模式转换跃迁也可能是机械敏感的，因此可能发挥作用。在轴突模型中被数学纳入，塑性阶段 Nav 响应引起的异位放电行为是周围神经病变的典型特征。在轻度泡状损伤的心肌细胞中，不可逆的 MS 调节（分别为 MS-Speed 和 MS-Number）导致的 Nav 和/或 Cav 渗漏，可能同样促进异位心律失常。在受损双层中病理性渗漏的 VGC 所在位置，通道周围双层的无序/流动性条件可能是抗心律失常 VGC 药物的一个重要“靶特征”。
