Functional role of Nav1.8 channels in action potentials of mouse CGRP-lineage dorsal root ganglion neurons
Abstract
Primary sensory neurons that sense noxious stimuli (nociceptors) are unusual in possessing two major components of voltage-dependent sodium channel current with different voltage dependence and kinetics. We used pharmacology to characterize the roles of defined sodium channel types in generating action potentials and controlling repetitive firing in putative peptidergic nociceptors, using mice in which CGRP-lineage neurons are fluorescently labelled. We found that the major components of sodium current were carried by Nav1.8 channels, identified by sensitivity to VX-548 (suzetrigine), and by Nav1.7 channels, identified by sensitivity to the toxin GsAF-1, with an additional smaller component of current carried by tetrodotoxin-sensitive channels resistant to GsAF-1. Action potential clamp experiments were used to quantify the size and time course of the Nav1.8 component of sodium current during firing of single and repetitive action potentials. In most neurons, Nav1.8 current carried the majority of overall sodium entry during action potentials and nearly all of the sodium current supporting action potentials during repetitive firing. Although total tetrodotoxin-sensitive current (mostly but not entirely carried by Nav1.7 channels) activated with smaller depolarizations and much more rapidly than Nav1.8 current, Nav1.8 current was equally important in setting the action potential threshold and was dominant in the action potential upstroke because of its greater size. By…
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