Impaired stretch modulation in potentially lethal cardiac sodium channel mutants

R1623Q and R1626P, slowly inactivating mutants of sodium channel, Nav1.5, associate with sporadic Long-QT3 (LQT3), a syndrome involving ventricular tachyarrhythmias and lethal cardio/respiratory disturbances. Cardiac mechanoelectric feedback is considered a factor in sporadic arrhythmias, and since stretch and shear forces modulate hNav1.5 gating, gating mechanics of LQT-Nav1.5 channels might provide insights. We compared recombinant R1623Q and WT currents in quiescent and stretched membrane of cell-attached patches of Xenopus oocytes. Macroscopic current was monitored before, during and after stretch induced by pipette suction. In either channel peak current at small depolarizations could be more than doubled by stretch. As in WT, R1623Q showed reversible stretch intensity dependent stretch-acceleration of current onset and decay at all voltages, with kinetic coupling between the two processes retained during stretch. The channels differed in the absolute extent of kinetic acceleration for a given stretch intensity; over a range of intensities, R1623Q inactivation speed increased significantly less than did WT. The LQT3 mutant R1626P also retained its kinetic coupling during stretch. Whereas stretch-difference currents in WT were mostly inhibitory, they were substantially (R1623Q) or entirely (R1626P) excitatory for the LQT3 mutants. If stretch-modulated Nav1.5 current (i.e. brief excitation followed by accelerated current decay) routinely contributes to cardiac mechanoelectric feedback, then during hemodynamic load variations, the abnormal stretch-modulated components of R1623Q and R1626P current could be perilously pro-arrhythmic.