The Excelsatoxin A-Receptor TMEM233 Modulates Nav1.8

  • FASEB J. 2026 Mar 31;40(6):e71706. doi: 10.1096/fj.202600787R.
George Oprita  1  2  3 ,  Marvin J A Meyer  1 ,  Daniel Rudolf  1 ,  Inês C A Pombeiro Stein  1 ,  Jennifer R Deuis  4 ,  Hue N T Tran  4 ,  Thomas Durek  5 ,  Klasfauseweh Tabea  4 ,  Jami Sina  4 ,  Stephen G Waxman  6  7  8 ,  Sulayman D Dib-Hajj  6  7  8 ,  Alexandru Babes  2 ,  Irina Vetter  4 ,  Andreas Leffler  1
Affiliations
  • 1. Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Lower Saxony, Germany.
  • 2. Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independent, Bucharest, Bucharest Municipality, Romania.
  • 3. National Center for Brain Research, Research Institute for Artificial Intelligence, Romanian Academy, Bucharest, Romania.
  • 4. Institute for Molecular Bioscience, The University of Queensland, Woolloongabba, Queensland, Australia.
  • 5. Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia.
  • 6. Department of Neurology, Yale University, New Haven, Connecticut, USA.
  • 7. Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
  • 8. Center for Neuroscience & Regeneration Research, Yale University, West Haven, Connecticut, USA.
PMID: 41854608 DOI: 10.1096/fj.202600787R
Abstract

The transmembrane protein (TMEM) 233 mediates Excelsatoxin A (ExTxA)-induced pain by removing fast inactivation of the Sodium Channel Nav1.7. In contrast, TMEM233 itself seems to stabilize the inactivated state of Nav1.7. ExTxA-induced activation of dorsal root ganglion (DRG) neurons is only partly inhibited by tetrodotoxin (TTX), possibly indicating that the TTX-resistant 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-induced calcium influx in DRG neurons was almost completely inhibited by TTX applied in combination with the selective Nav1.8-inhibitor suzetrigine (VX-548). ExTxA removed fast inactivation of TTX-resistant sodium currents in DRG neurons, as well as of recombinant human or rat Nav1.8 channels co-expressed with TMEM233 in ND7/23 or CHO cells. The co-expression of Nav1.8 and TMEM233 was associated with an ExTxA-independent hyperpolarizing shift of the voltage-dependencies of fast and slow inactivation, an impeded recovery from fast inactivation and an increased use-dependent inhibition by the local anesthetic lidocaine. These effects were constant across physiological temperatures (~10°C, 21°C and 37°C), and TMEM233 also modulated temperature-dependent properties of Nav1.8. Our data suggest that ExTxA-induced pain is likely to involve a TMEM233-mediated 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.

Keywords
Nav1.8; TMEM233; excelsatoxin; pain; sensory neurons.
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