Compartment-specific regulation of Na_V1.7 in sensory neurons after acute exposure to TNF-α

Tumor necrosis factor α (TNF-α) is a major pro-inflammatory cytokine, important in many diseases, that sensitizes nociceptors through its action on a variety of ion channels, including voltage-gated sodium (Na_V) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel Na_V1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on Na_V1.7 is mediated by p38 MAPK and identify serine 110 in the channel's N terminus as the phospho-acceptor site, which triggers Na_V1.7 channel insertion into the somatic membrane. We also show that the N terminus of Na_V1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases Na_V1.7-carrying vesicle accumulation at axonal endings, we did not observe increased channel insertion into the axonal membrane. These results identify molecular determinants of TNF-α-mediated regulation of Na_V1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane.