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In contrast, TMEM233 itself seems to stabilize the inactivated state of Nav1.7. ExTxA\u2010induced activation of dorsal root ganglion (DRG) neurons is only partly inhibited by tetrodotoxin (TTX), possibly indicating that the TTX\u2010resistant sodium channel Nav1.8 is also modulated by ExTxA. To address this possibility, we performed patch clamp and calcium imaging experiments on mouse DRG neurons and on neuroblastoma ND7\/23 and CHO cells expressing Nav1.8 and TMEM233. ExTxA\u2010induced calcium influx in DRG neurons was almost completely inhibited by TTX applied in combination with the selective Nav1.8\u2010inhibitor suzetrigine (VX\u2010548). ExTxA removed fast inactivation of TTX\u2010resistant sodium currents in DRG neurons, as well as of recombinant human or rat Nav1.8 channels co\u2010expressed with TMEM233 in ND7\/23 or CHO cells. The co\u2010expression of Nav1.8 and TMEM233 was associated with an ExTxA\u2010independent hyperpolarizing shift of the voltage\u2010dependencies of fast and slow inactivation, an impeded recovery from fast inactivation and an increased use\u2010dependent inhibition by the local anesthetic lidocaine. These effects were constant across physiological temperatures (~10\u00b0C, 21\u00b0C and 37\u00b0C), and TMEM233 also modulated temperature\u2010dependent properties of Nav1.8. Our data suggest that ExTxA\u2010induced pain is likely to involve a TMEM233\u2010mediated regulation of Nav1.8. Furthermore, TMEM233 seems to be a relevant interacting protein of Nav1.8 that modulates the channel's distinct functional and pharmacological properties. These data warrant further investigations into how TMEM233 regulates nociceptor excitability.<\/jats:p>","DOI":"10.1096\/fj.202600787r","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T15:24:21Z","timestamp":1773933861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Excelsatoxin A\u2010Receptor\n                    <scp>TMEM233<\/scp>\n                    Modulates Nav1.8"],"prefix":"10.1096","volume":"40","author":[{"given":"George","family":"Oprita","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School  Hannover Lower Saxony Germany"},{"name":"Department of Anatomy, Physiology and Biophysics, Faculty of Biology University of Bucharest, Splaiul Independent  Bucharest Bucharest Municipality Romania"},{"name":"National Center for Brain Research, Research Institute for Artificial Intelligence Romanian Academy  Bucharest Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin J. 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