Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch

¹ Ottawa Health Research Institute
² Ottawa Health Research Inst

^* To whom correspondence should be addressed. E-mail: cmorris{at}ohri.ca.

Submitted on November 15, 2006
Revised on January 2, 2007
Accepted on 13 March 2007

	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 ()-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/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 (~1.30-1.85 -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; Laitko & Morris 2004, JGP) 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 if 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.

Key Words: bilayer mechanics,, lateral pressure profile,, mechanosensitive,, mechanotransduction, sodium channel,, stretch sensitive,