Compartment-specific regulation of Na1.7 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) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel Na1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on Na1.7 is mediated by p38 MAPK and identify serine 110 in the channel's N terminus as the phospho-acceptor site, which triggers Na1.7 channel insertion into the somatic membrane. We also show that the N terminus of Na1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases Na1.7-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 Na1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane.