Tetrodotoxin-resistant voltage-gated sodium channels (TTX-R VGSCs)

Tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels, primarily comprising the Nav1.8 (SCN10A) and Nav1.9 (SCN11A) isoforms, are critical mediators of excitability in peripheral sensory neurons [PMID: 23333502]. These channels are predominantly expressed in the dorsal root ganglion (DRG) and trigeminal ganglion, where they play a fundamental role in the initiation and propagation of action potentials in nociceptors [PMID: 24021961]. Unlike TTX-sensitive channels, Nav1.8 and Nav1.9 exhibit distinct kinetic properties, such as slow inactivation, which allow them to support repetitive firing during sustained noxious stimuli or inflammatory states [PMID: 10433265]. Their restricted expression in the peripheral nervous system makes them highly attractive therapeutic targets for treating chronic pain conditions, such as neuropathic and inflammatory pain, with a reduced risk of central nervous system or cardiac side effects [PMID: 38570519]. Recent clinical developments, such as the selective Nav1.8 inhibitor suzetrigine (VX-548), have demonstrated the potential for these channels to provide effective analgesia without the addictive properties or respiratory risks associated with opioids [Vertex Pharmaceuticals, 2024].

Other names

Nav1.8Nav1.9SCN10ASCN11ASodium channel protein type 10 subunit alphaSodium channel protein type 11 subunit alphaPeripheral nerve-type 3 (PN3)Sensory neuron-specific (SNS) sodium channelNaN (Sodium channel alpha-subunit Next)

Blockade of the alpha-subunit pore of Nav1.8 and Nav1.9 channels, which prevents the influx of sodium ions required for membrane depolarization, thereby inhibiting the generation and conduction of pain-related action potentials in peripheral sensory neurons [PMID: 23333502].