The Excelsatoxin A-Receptor TMEM233 Modulates Nav1.8

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Transmembrane protein 233 (TMEM233) is implicated in Excelsatoxin A (ExTxA)-induced pain via modulation of the sodium channel Nav1.7.
• ExTxA-induced dorsal root ganglion (DRG) neuron activation is partially resistant to tetrodotoxin (TTX), suggesting involvement of TTX-resistant sodium channels like Nav1.8.

Purpose of the Study:

• To investigate the role of TMEM233 and its interaction with the sodium channel Nav1.8 in ExTxA-induced pain.
• To characterize the functional and pharmacological consequences of TMEM233 co-expression with Nav1.8.

Main Methods:

• Patch clamp electrophysiology and calcium imaging were performed on mouse DRG neurons and heterologous cell systems (ND7/23, CHO) expressing Nav1.8 and TMEM233.
• Pharmacological agents including TTX and the selective Nav1.8 inhibitor suzetrigine (VX-548) were used to dissect channel contributions.

Main Results:

• ExTxA-induced calcium influx in DRG neurons was significantly reduced by combined TTX and suzetrigine, confirming Nav1.8 involvement.
• Co-expression of Nav1.8 and TMEM233 resulted in ExTxA-induced removal of fast inactivation in TTX-resistant sodium currents.
• TMEM233 co-expression with Nav1.8 led to altered channel gating, impaired recovery from inactivation, and increased sensitivity to lidocaine, independent of ExTxA stimulation.

Conclusions:

• TMEM233 plays a significant role in ExTxA-induced pain by modulating the Nav1.8 sodium channel.
• TMEM233 is a key interacting protein that alters the functional and pharmacological properties of Nav1.8.
• These findings highlight TMEM233 as a potential therapeutic target for managing pain associated with Nav1.8 channel activity.