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Nav Channel Mechanosensitivity: Activation and Inactivation Accelerate Reversibly with Stretch

Neuroscience, Ottawa Health Research Institute, Ottawa, Ontario, Canada

Correspondence: Ottawa Hospital, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4E9. Tel.: 613-798-5555, ext. 18608; Fax: 613-761-5330; E-mail: cmorris{at}ohri.ca.

Voltage-gated sodium channels (Nav) are modulated by many bilayer mechanical amphiphiles, but whether, like other voltage-gated channels (Kv, HCN, Cav), they respond to physical bilayer deformations is unknown. We expressed human heart Nav1.5 pore -subunit in oocytes (where, unlike Nav1.4, Nav1.5 exhibits normal kinetics) and measured small macroscopic currents in cell-attached patches. Pipette pressure was used to reversibly stretch the membrane for comparison of I_Na(t) before, during, and after stretch. At all voltages, and in a dose-dependent fashion, stretch accelerated the I_Na(t) time course. The sign of membrane curvature was not relevant. Typical stretch stimuli reversibly accelerated both activation and inactivation by 1.4-fold; normalization of peak I_Na(t) followed by temporal scaling (1.30- to 1.85-fold) resulted in full overlap of the stretch/no-stretch traces. Evidently the rate-limiting outward voltage sensor motion in the Nav1.5 activation path (as in Kv1) accelerated with stretch. Stretch-accelerated inactivation occurred even with activation saturated, so an independently stretch-modulated inactivation transition is also a possibility. Since Nav1.5 channel-stretch modulation was both reliable and reversible, and required stretch stimuli no more intense than what typically activates putative mechanotransducer channels (e.g., stretch-activated TRPC1-based currents), Nav channels join the ranks of putative mechanotransducers. It is noteworthy that at voltages near the activation threshold, moderate stretch increased the peak I_Na amplitude 1.5-fold. It will be important to determine whether stretch-modulated Nav current contributes to cardiac arrhythmias, to mechanosensory responses in interstitial cells of Cajal, to touch receptor responses, and to neuropathic (i.e., hypermechanosensitive) and/or normal pain reception.