Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Tyagi S

PROVIDER: S-EPMC10947185 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Tyagi Sidharth S Higerd-Rusli Grant P GP Ghovanloo Mohammad-Reza MR Dib-Hajj Fadia F Zhao Peng P Liu Shujun S Kim Dong-Hyun DH Shim Ji Seon JS Park Kang-Sik KS Waxman Stephen G SG Choi Jin-Sung JS Dib-Hajj Sulayman D SD

Cell reports 20240122 2

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 an ...[more]

PMID: 38261513

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Project description:Background and purposePharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Nav 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Nav 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav channel mutants is still unknown.Experimental approachWe used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Nav 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels.Key resultsIn a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Nav 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 μM) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Nav 1.7-I234T channels, compared with neurons expressing the normal channels (Nav 1.7-WT). Pre-incubation with 30 μM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Nav 1.7-I234T channels. Although the expected use-dependent inhibition of Nav 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Nav 1.7-I234T mutant channels.Conclusion and implicationsThese results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants.Linked articlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Dataset Information

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

Publications

Compartment-specific regulation of Na<sub>V</sub>1.7 in sensory neurons after acute exposure to TNF-α.

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