A tetrodotoxin-sensitive voltage-gated sodium ion channel alpha subunit predominantly expressed in peripheral pain-sensing neurons (nociceptors) and sympathetic ganglion neurons, where it acts as a threshold amplifier for action potential initiation. Human genetics cemented Nav1.7 as a master switch for pain perception: in 2004, Yong Yang and colleagues showed that gain-of-function mutations in its encoding gene SCN9A cause inherited primary erythromelalgia, and in 2006, James Cox, C. Geoffrey Woods, and colleagues demonstrated that homozygous loss-of-function SCN9A mutations cause complete congenital insensitivity to pain without impairing intelligence or touch.
Nav1.7 is a single 1,988-amino-acid polypeptide chain organized into four homologous repeat domains (DI, DII, DIII, and DIV), each containing six transmembrane alpha-helices (S1–S6). Near-atomic cryo-electron microscopy structures resolve the four-domain arrangement and selective pore blocker binding sites.
In each domain, segments S1–S4 form a peripheral voltage-sensing domain (VSD) with positively charged arginine and lysine residues along the S4 helix, while the S5–S6 helices and their re-entrant P-loops assemble at the center to create the selective sodium-conducting pore and the DEKA selectivity filter.
A conserved intracellular loop linking domains DIII and DIV (carrying the hydrophobic IFM motif) acts as the fast-inactivation gate that occludes the intracellular pore mouth within milliseconds of channel opening.
Function
In patch-clamp electrophysiology recordings, Nav1.7 displays slow closed-state inactivation combined with fast activation and recovery. When a noxious thermal, mechanical, or inflammatory stimulus produces a small, slow subthreshold generator potential in free nerve endings of nociceptors, Nav1.7 opens to generate a "ramp current" that amplifies the depolarization until it reaches the higher voltage threshold required to fire Nav1.8 and propagate an action potential into the spinal dorsal horn. In olfactory receptor neurons, Nav1.7 is similarly required for synaptic transmission at the first synapse in the olfactory bulb.
Regulation
Inflammatory mediators such as prostaglandin E2 and nerve growth factor (NGF) activate protein kinase C and ERK1/2 (MAPK/ERK cascade), which phosphorylate intracellular loops of Nav1.7 to shift its activation voltage hyperpolarizing-ward and increase nociceptor excitability.
Surface density at the axon initial segment and peripheral terminals is regulated by NEDD4-2 (NEDD4L) ubiquitination and endocytic recycling.
Interactions
Co-expressed in peripheral sensory neurons with TRPV1 capsaicin/heat receptors and the tetrodotoxin-resistant sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A), while sparing cardiac Nav1.5 (SCN5A) and central Nav1.2 (SCN2A).
Clinical Relevance
Bi-directional human pain channelopathies: Gain-of-function missense mutations in SCN9A that hyperpolarize activation cause inherited erythromelalgia (burning extremity pain triggered by warmth), whereas mutations that impair fast inactivation cause paroxysmal extreme pain disorder (PEPD). Conversely, biallelic loss-of-function mutations cause congenital insensitivity to pain (CIP) paired only with anosmia (loss of smell).
Non-opioid analgesic target: Because non-selective sodium channel blockers (such as lidocaine) also inhibit cardiac Nav1.5 and central channels, modern drug discovery targets the isoform-specific VSD4 voltage-sensor pocket of Nav1.7/Nav1.8, as well as dorsal-root-ganglion antisense oligonucleotides, siRNAs, and epigenetic dCas9 (CRISPR-Cas9) repressors aimed at durable non-opioid pain relief.