Nav1.7

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SCN9A
PDB 1byy EBI.jpg
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSCN9A, ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1, SFNP, sodium voltage-gated channel alpha subunit 9
External IDsMGI: 107636 HomoloGene: 2237 GeneCards: SCN9A
Gene location (Human)
Chromosome 2 (human)
Chr.Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for SCN9A
Genomic location for SCN9A
Band2q24.3Start166,195,185 bp[1]
End166,376,001 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

6335

20274

Ensembl

ENSG00000169432

ENSMUSG00000075316

UniProt

Q15858

Q62205

RefSeq (mRNA)

NM_002977
NM_001365536

NM_001290674
NM_001290675
NM_018852

RefSeq (protein)

NP_002968
NP_001352465

NP_001277603
NP_001277604

Location (UCSC)Chr 2: 166.2 – 166.38 MbChr 2: 66.48 – 66.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[5][6][7] It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.[8][9]

Function[edit]

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 the region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which are 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 the level of tetrodotoxin.[10] Nav1.7 is important in the early phases of neuronal electrogenesis. Nav1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree.[11] This property allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes.[11] This brings neurons to a 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.[12]

Clinical significance[edit]

Animal studies[edit]

The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice. These transgenic mice specifically lack Nav1.7 in Nav1.8 positive nociceptors and showed reduced behavioural responses, specifically to acute mechanical and inflammatory pain assays. At the same time, behavioural responses to acute thermal and neuropathic pain assays remained intact.[13] However, the expression of Nav1.7 is not restricted to Nav1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Nav1.7 in all DRG neurons and the other lacking Nav1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons.[14] Therefore, Nav1.7 expressed in Nav1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays. Finally, Nav1.7 expressed in sympathetic neurons is critical for normal behavioural responses to neuropathic pain assays.

Primary erythromelalgia[edit]

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. Multiple studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia.[15][16] 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.[17] 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.[9] Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.[18]

Paroxysmal extreme pain disorder[edit]

Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder.[19][20] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.[19][20]

Congenital insensitivity to pain[edit]

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,[21] 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 causes loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutations observed were nonsense mutation, with the majority of affected patients having a homozygous mutation in the SCN9A gene. This discovery linked loss of Nav1.7 function with the inability to experience pain. This is in contrast with the genetic basis of primary erythromelalgia in which the disorder results from gain-of-function mutations.[18]

Clinical analgesics[edit]

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.[22][23] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling.[22][24] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.[22] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.[25][26]

Itch[edit]

Mutations of Nav1.7 have been linked to itching (pruritus),[27][28] and genetic knockouts of Nav1.7[29] and an antibody that inhibits Nav1.7 also appear to inhibit itching.[30][31][32]

Future prospects[edit]

As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[20] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[33] Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.[33][34][35]

A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (TV-45070, XEN402), PF-05089771, DSP-2230, NKTR-171, GDC-0276, and RG7893 (GDC-0287).[36][37][38] Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.[39]

Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics.[40] Recently, it has been elucidated that congenital loss of Navv1.7 results in a dramatic increase in the levels of endogenous enkephalins, and it was found that blocking these opioids with the opioid antagonist naloxone allowed for pain sensitivity both in Navv1.7 null mice and in a woman with a defective Navv1.7 gene and associated congenital insensitivity to pain.[40] Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models.[41][unreliable medical source] It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Nav 1.7-mediated sodium efflux is necessary to upregulate enkephalin expression enough to achieve complete analgesia. Prior to the development of JNJ63955, the most potent [Nav 1.7] antagonists had failed in regards to achieving the same degree of analgesia as congenital Nav 1.7 inactivity.[40] The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors.[40] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.[40]

An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.[40]

References[edit]

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Further reading[edit]

External links[edit]

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