Sodium channel, voltage-gated, type IX, alpha subunit
PDB rendering based on 1byy.
Available structures PDB Identifiers Symbols External IDs GeneCards: Gene Ontology Molecular function •
Cellular component •
Biological process •
Sources: Amigo / QuickGO Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) PubMed search
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons, the nociceptive neurons at dorsal root ganglion (DRG) and trigeminal ganglion, and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.
Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to level of tetrodotoxin. Nav1.7 is important in early phases of neuronal electrogenesis. Nav1.7 is described by slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. This property that allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. This brings neurons to certain voltage that stimulate Nav1.8, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.
Clues that Nav1.7 is involved in pain is originated from the observation that DRG neurons in animal models in inflammatory pain showed increase response to Nav1.7. Also knockout mice that lack Nav1.7 in nociceptors showed reduced response to inflammatory pain. However, neuropathic pain(chronic pain resulting from injury to the nervous system) remained intact. These results are consistent with an important role of Nav1.7 in setting the inflammatory pain threshold. To observe the role of Nav1.7 in relation to other sodium channels expressed in peripheral sensory neurons, the researchers created mice deficient in both Nav1.7 and Nav1.8 channels. Mice deficient in Nav1.8 had deficits in sensing inflammatory pain (initiated by tissue damage/inflammation) and visceral pain (initiated by damage or injury to internal organs) but not neuropathic pain. The thermal pain threshold in mice deficient in both Nav1.7 and Nav1.8 mice was twice that of mice lacking only Nav1.7. The result clearly implicate Nav1.7 as a major sodium channel in peripheral nociception and suggest a functional link to Nav1.8.
Mutation in Nav1.7 may result in primary erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Many studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. All of the observed erythromelalgia mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated. In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain hyperalgesia. While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons. Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.
Insensitivity to pain
Individuals with congenital insensitivity to pain have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, and are often only diagnosed because of limping or lack of use of a limb. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.
A mutation that caused loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutation observed were nonsense mutation with majority of affected patients having homozygous mutation in the SCN9A gene. Their observation linked loss of Nav1.7 function with incapability to experience pain. The result was in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations.
The association of pain insensitivity with the loss of function of a certain sodium channel may have therapeutic applications. Since Nav1.7 is not present in cardiac muscle or neurons in the central nervous system, blockers of Nav1.7 will not have direct action on these cells and thus can have less side effects than current pain medications.
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Ca2+: Calcium channelLigand-gated Na+: Sodium channelConstitutively activeProton gated K+: Potassium channelKvα1-6 (1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8) · (2.1, 2.2) · (3.1, 3.2, 3.3, 3.4) · (4.1, 4.2, 4.3) · (5.1) · (6.1, 6.2, 6.3, 6.4)
Kvα7-12 (7.1, 7.2, 7.3, 7.4, 7.5) · (8.1, 8.2) · (9.1, 9.2, 9.3) · (10.1, 10.2) · (11.1/hERG, 11.2, 11.3) · (12.1, 12.2, 12.3)
Kvβ (1, 2, 3) · KCNIP (1, 2, 3, 4) · minK/ISK · minK/ISK-like · MiRP (1, 2, 3) · Shaker gene
OtherCl-: Chloride channelHVCN1General see also disorders
B memb: cead, trns (1A, 1C, 1F, 2A, 3A1, 3A2-3, 3D), othr
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