Perturbed voltage-gated channel activity in perturbed bilayers: implications for ectopic arrhythmias arising from damaged membrane.

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.