Tetrodotoxin-resistant neuronal voltage-gated sodium channel (TTX-r Nav)

Tetrodotoxin-resistant (TTX-r) neuronal voltage-gated sodium channels, primarily comprising the Nav1.8 (SCN10A) and Nav1.9 (SCN11A) isoforms, are specialized ion channels essential for the transmission of pain signals in the peripheral nervous system [nih.gov, guidetopharmacology.org]. Unlike most other sodium channels, these isoforms are relatively insensitive to the pufferfish toxin tetrodotoxin and are almost exclusively expressed in the small-diameter sensory neurons of the dorsal root ganglia [wikipedia.org, nih.gov]. Nav1.8 plays a dominant role in the upstroke of action potentials in nociceptors, especially during cold or inflammatory conditions, while Nav1.9 contributes to setting the resting membrane potential and the threshold for firing [nih.gov, frontiersin.org]. Because of their restricted peripheral expression, these channels are highly attractive therapeutic targets for treating chronic, inflammatory, and neuropathic pain without the central nervous system side effects associated with opioids, such as addiction or respiratory depression [vrtx.com, nih.gov]. Recent clinical success has been achieved with suzetrigine (VX-548), a first-in-class selective Nav1.8 inhibitor that utilizes an allosteric mechanism to stabilize the channel in its closed state [vrtx.com, researchgate.net].

Other names

Tetrodotoxin-resistant sodium channelsTTX-r VGSCsNav1.8Nav1.9SCN10ASCN11APeripheral tetrodotoxin-resistant sodium channels

Selective inhibition of sodium ion conductance through the channel pore or allosteric stabilization of the inactivated/closed state, thereby reducing the excitability of nociceptive neurons and preventing the transmission of pain signals to the central nervous system [vrtx.com, nih.gov].