Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α

• Published in: Cell reports (Cambridge) 2024-02, Vol.43 (2), p.113685-113685, Article 113685
• Main Authors: Tyagi, Sidharth, Higerd-Rusli, Grant P., Ghovanloo, Mohammad-Reza, Dib-Hajj, Fadia, Zhao, Peng, Liu, Shujun, Kim, Dong-Hyun, Shim, Ji Seon, Park, Kang-Sik, Waxman, Stephen G., Choi, Jin-Sung, Dib-Hajj, Sulayman D.
• Format: Article
• Language: English
• Subjects: CP: Neuroscience; distal axons; inflammatory pain; NaV1.7; neuronal compartments; soma; TNF-α
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113685

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 (NaV) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel NaV1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on NaV1.7 is mediated by p38 MAPK and identify serine 110 in the channel’s N terminus as the phospho-acceptor site, which triggers NaV1.7 channel insertion into the somatic membrane. We also show that the N terminus of NaV1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases NaV1.7-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 NaV1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane. [Display omitted] •Acute exposure to TNF-α increases NaV1.7 current density and neuronal excitability•Increased NaV1.7 current density occurs through p38 MAPK phosphorylation of residue Ser110•TNF-α exposure increases delivery of vesicles carrying NaV1.7 channels to distal axons•Insertion of NaV1.7 channels is differentially regulated in DRG axons compared to somas TNF-α is a major cytokine involved in inflammatory pain. Tyagi et al. show that TNF-α causes increased membrane insertion of NaV1.7, a sodium channel linked to pain disorders, in a p38 MAPK-dependent manner; however, this process is differentially regulated in DRG axons vs. somas.