SCN9A
Domain
The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.
Function
Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na(+) ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:17167479, PubMed:19369487, PubMed:24311784, PubMed:25240195, PubMed:26680203, PubMed:7720699). Nav1.7 plays a crucial role in controlling the excitability and action potential propagation from nociceptor neurons, thereby contributing to the sensory perception of pain (PubMed:17145499, PubMed:17167479, PubMed:19369487, PubMed:24311784).
Involvement in disease
Primary erythermalgia
PERYTHM
Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands.
None
The disease is caused by variants affecting the gene represented in this entry.
Indifference to pain, congenital, autosomal recessive
CIP
A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating.
None
The disease is caused by variants affecting the gene represented in this entry.
Paroxysmal extreme pain disorder
PEXPD
An autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents.
Ubiquitinated by NEDD4L; which may promote its endocytosis.
Sequence Similarities
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.7/SCN9A subfamily.
Tissue Specificity
Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Also expressed in vagus nerves within the head and neck region (PubMed:31647222). Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Cell projection
- Neuron projection
- Cell projection
- Axon
- Localizes to neuron terminals (PubMed:30765606, PubMed:30795902). Also detected at Nodes of Ranvier (PubMed:30795902).
Alternative names
NENA, SCN9A, Sodium channel protein type 9 subunit alpha, Neuroendocrine sodium channel, Peripheral sodium channel 1, Sodium channel protein type IX subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.7, hNE-Na, PN1