The Excelsatoxin A-Receptor TMEM233 Modulates Nav1.8
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.…
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