Oxidation differentially modulates the recombinant voltage-gated Na+ channel α-subunits Nav1.7 and Nav1.8

- The sensory neuronal Na+ channels Nav1.7 and Nav1.8 are modulated by oxidation.
- Oxidation induces non-inactivating persistent currents on Nav1.7 and Nav1.8.
- Oxidized Nav1.7 and Nav1.8 generate large ramp currents upon slow depolarizations.
- Slow inactivation of Nav1.7 and Nav1.8 is not modulated by oxidation.

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 500 µM induced a shift of the voltage-dependency of activation towards more hyperpolarized potentials. While fast inactivation was stabilized by 100 µM ChT, it was partially removed by 500 µM ChT on both α-subunits (Nav1.7