Voltage-gated sodium channel (Tetrodotoxin-resistant) (Nav (TTX-r))

Voltage-gated sodium channels (VGSCs) that are resistant to tetrodotoxin (TTX), specifically Nav1.8 (encoded by SCN10A) and Nav1.9 (encoded by SCN11A), are predominantly expressed in the peripheral nervous system, particularly within the dorsal root ganglion (DRG) neurons [Dib-Hajj et al., 2010; Bennett et al., 2019]. These channels play a critical role in the transmission of nociceptive (pain) signals; Nav1.8 is responsible for the majority of the inward current during the action potential upstroke in small-diameter sensory neurons, while Nav1.9 regulates the resting membrane potential and threshold for firing [Bennett et al., 2019; Waxman, 2013]. Because of their restricted expression in nociceptors and their essential role in pain signaling, they are highly attractive targets for the development of non-opioid analgesics [Waxman, 2013]. Mutations in the genes encoding these channels are linked to various pain disorders, including small fiber neuropathy and congenital insensitivity to pain [Dib-Hajj et al., 2010; Bennett et al., 2019]. Therapeutic strategies focus on small-molecule inhibitors that selectively block these channels to provide pain relief without the central nervous system side effects or addiction potential associated with opioids [Vertex Pharmaceuticals, 2024]. Recent clinical successes, such as with the Nav1.8 inhibitor suzetrigine (VX-548), highlight the potential of this target class in treating both acute and neuropathic pain conditions [Vertex Pharmaceuticals, 2024].

Other names

Tetrodotoxin-resistant sodium channelsTTX-r NavSodium channel protein type 10 subunit alpha (Nav1.8)Sodium channel protein type 11 subunit alpha (Nav1.9)SCN10ASCN11APeripheral nerve sodium channel 3 (PN3)Sensory neuron-specific sodium channel (SNS)Sodium channel asparagine-rich (NaN)

Selective inhibition of TTX-resistant sodium channels (primarily Nav1.8 and Nav1.9) blocks the influx of sodium ions into nociceptive neurons, thereby preventing the initiation and propagation of pain signals to the central nervous system [Bennett et al., 2019; Waxman, 2013].