title: Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch.
abstract: 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 alpha-subunit in oocytes (where, unlike alphaNav1.4, alphaNav1.5 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 approximately 1.4-fold; normalization of peak I(Na)(t) followed by temporal scaling ( approximately 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 approximately 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.
authors.affiliation: Neuroscience, Ottawa Health Research Institute, Ottawa, Ontario, Canada. cmorris@ohri.ca
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Morris
authors.forename: Peter F
authors.initials: PF
authors.lastname: Juranka
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007700:Kinetics; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels