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Oxidation differentially modulates the recombinant voltage-gated Na(+) channel α-subunits Nav1.7 and Nav1.8.
Brain Research 2016 October 2
Voltage-gated Na(+) channels regulate neuronal excitability by generating the upstroke of action potentials. The α-subunits Nav1.7 and Nav1.8 are required for normal function of sensory neurons and thus for peripheral pain processing, but also for an increased excitability leading to an increased pain sensitivity under several conditions associated with oxidative stress. While little is known about the direct effects of oxidants on Nav1.7 and Nav1.8, a recent study on mouse dorsal root ganglion neurons suggested that oxidant-induced alterations of nociceptor excitability are primarily driven by Nav1.8. Here we performed whole-cell patch clamp recordings to explore how oxidation modulates functional properties of recombinant Nav1.7 and Nav1.8 channels. The strong oxidant chloramine-T (ChT) at 100 and 500µM induced a shift of the voltage-dependency of activation towards more hyperpolarized potentials. While fast inactivation was stabilized by 100µM ChT, it was partially removed by 500µM ChT on both α-subunits (Nav1.7<Nav1.8) and enabled them to produce large non-inactivating persistent currents as well as prominent ramp currents. Slow inactivation of both peak and persistent currents for both Nav1.7 and Nav1.8 were stabilized by ChT. Our data demonstrate that oxidation promotes gating of Nav1.7 and Nav1.8 by reducing the threshold for activation and by abrogating fast inactivation. The resulting persistent currents are regulated by slow inactivation and appear to be more prominent for Nav1.8 as compared to Nav1.7.
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