UniProt functional annotation for Q15858



	UniProt functional annotation for Q15858

UniProt code: Q15858.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}.

Activity regulation: Inhibited by tetrodotoxin (PubMed:23077250). Weakly inhibited by saxitoxin (PubMed:23077250). {ECO:0000269|PubMed:23077250}.

Subunit: The sodium channel complex consists of a large, channel- forming alpha subunit (SCN9A) regulated by one or more beta subunits (SCN1B, SCN2B, SCN3B and SCN4B) (PubMed:7720699, PubMed:17167479, PubMed:25240195). SCN1B and SCN3B are non-covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A. Interacts with NEDD4 and NEDD4L (By similarity). Interacts with the scorpion alpha- toxin CvIV4 (PubMed:21887265). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider huwentoxin-IV (through the extracellular loop S3-S4 of repeat II) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider protoxin-II (through the extracellular loop S3-S4 of repeats II and IV) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider beta/delta-theraphotoxin- Pre1a (PubMed:28428547). {ECO:0000250|UniProtKB:Q62205, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:21659528, ECO:0000269|PubMed:21887265, ECO:0000269|PubMed:24497506, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:28428547, ECO:0000269|PubMed:30661758, ECO:0000269|PubMed:30765606, ECO:0000269|PubMed:7720699}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}; Multi-pass membrane protein {ECO:0000250|UniProtKB:D0E0C2}. Cell projection, neuron projection {ECO:0000250|UniProtKB:O08562}. Note=In neurite terminals. {ECO:0000250|UniProtKB:O08562}.

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. {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15302875, ECO:0000269|PubMed:31647222, ECO:0000269|PubMed:7720699, ECO:0000269|PubMed:9169448}.

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. {ECO:0000305}.

Ptm: Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents. {ECO:0000269|PubMed:25240195}.

Ptm: Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4. {ECO:0000250|UniProtKB:Q62205}.

Disease: Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:16702558, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: 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. {ECO:0000269|PubMed:20635406}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: 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. {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:25285947}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.7/SCN9A subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). {ECO:0000269\|PubMed:15178348, ECO:0000269\|PubMed:15385606, ECO:0000269\|PubMed:16988069, ECO:0000269\|PubMed:17145499, ECO:0000269\|PubMed:17167479, ECO:0000269\|PubMed:19369487, ECO:0000269\|PubMed:24311784, ECO:0000269\|PubMed:25240195, ECO:0000269\|PubMed:26680203, ECO:0000269\|PubMed:7720699}.


Activity regulation:		Inhibited by tetrodotoxin (PubMed:23077250). Weakly inhibited by saxitoxin (PubMed:23077250). {ECO:0000269\|PubMed:23077250}.
Subunit:		The sodium channel complex consists of a large, channel- forming alpha subunit (SCN9A) regulated by one or more beta subunits (SCN1B, SCN2B, SCN3B and SCN4B) (PubMed:7720699, PubMed:17167479, PubMed:25240195). SCN1B and SCN3B are non-covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A. Interacts with NEDD4 and NEDD4L (By similarity). Interacts with the scorpion alpha- toxin CvIV4 (PubMed:21887265). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider huwentoxin-IV (through the extracellular loop S3-S4 of repeat II) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider protoxin-II (through the extracellular loop S3-S4 of repeats II and IV) (PubMed:20855463, PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the spider beta/delta-theraphotoxin- Pre1a (PubMed:28428547). {ECO:0000250\|UniProtKB:Q62205, ECO:0000269\|PubMed:17167479, ECO:0000269\|PubMed:21659528, ECO:0000269\|PubMed:21887265, ECO:0000269\|PubMed:24497506, ECO:0000269\|PubMed:25240195, ECO:0000269\|PubMed:28428547, ECO:0000269\|PubMed:30661758, ECO:0000269\|PubMed:30765606, ECO:0000269\|PubMed:7720699}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:15385606, ECO:0000269\|PubMed:17167479, ECO:0000269\|PubMed:19369487, ECO:0000269\|PubMed:24311784, ECO:0000269\|PubMed:25240195, ECO:0000269\|PubMed:26680203, ECO:0000269\|PubMed:7720699}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:D0E0C2}. Cell projection, neuron projection {ECO:0000250\|UniProtKB:O08562}. Note=In neurite terminals. {ECO:0000250\|UniProtKB:O08562}.
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. {ECO:0000269\|PubMed:15178348, ECO:0000269\|PubMed:15302875, ECO:0000269\|PubMed:31647222, ECO:0000269\|PubMed:7720699, ECO:0000269\|PubMed:9169448}.
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. {ECO:0000305}.
Ptm:		Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents. {ECO:0000269\|PubMed:25240195}.
Ptm:		Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4. {ECO:0000250\|UniProtKB:Q62205}.
Disease:		Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269\|PubMed:14985375, ECO:0000269\|PubMed:15385606, ECO:0000269\|PubMed:15955112, ECO:0000269\|PubMed:15958509, ECO:0000269\|PubMed:16216943, ECO:0000269\|PubMed:16392115, ECO:0000269\|PubMed:16702558, ECO:0000269\|PubMed:16988069, ECO:0000269\|PubMed:18945915, ECO:0000269\|PubMed:19369487, ECO:0000269\|PubMed:24311784}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: 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. {ECO:0000269\|PubMed:20635406}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: 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. {ECO:0000269\|PubMed:17145499, ECO:0000269\|PubMed:18945915, ECO:0000269\|PubMed:25285947}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.7/SCN9A subfamily. {ECO:0000305}.