NaV1.9: a sodium channel linked to human pain

Abstract

The voltage-gated sodium channel Na(V)1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting Na(V)1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans--two genetic and functional studies in rare genetic disorders, and a third study showing a role for Na(V)1.9 in painful peripheral neuropathy--have demonstrated that Na(V)1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain.

Familial gain-of-function Nav1.9 mutation in a painful channelopathy

“…While a large number of mutations in Na v 1.7 have been linked to pain disorders in humans, fewer mutations in Na v 1.9 have been described thus far 26. Interestingly, gain-of-function mutations in Na v 1.9 have been linked to painful12–15 and painless channelopathies 16–18.…”

A Gain-of-Function Mutation in Nav1.6 in a Case of Trigeminal Neuralgia

“…Rare and common painful disorders, but not TN, have been genetically and functionally linked to gain-of-function mutations in peripheral sodium channels Na V 1.7, Na V 1.8 and Na V 1.9 (14)(15)(16). Although gain-of-function mutations of Na V 1.6 have been shown to cause infantile epileptic encephalopathy (17)(18)(19), there has been no genetic evidence thus far for a role for this channel in human pain disorders.…”

Pain insensitivity: distal S6-segment mutations in NaV1.9 emerge as critical hotspot

“…Gain of function mutations in the sensory neuronspecific voltage-gated sodium channel Na V 1.9/SCN11A lead to entirely opposite pain phenotypes, i.e., congenital pain insensitivity or severe and episodic neuropathic pain [1,2]. The explanation for the discrepancy in the clinical outcome, such as the location of the mutation within the ion-channel, remains elusive.…”