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{{protein
{{DISPLAYTITLE:Na<sub>v</sub>1.7}}
| Name = sodium channel, voltage-gated, type IX, alpha
{{Infobox_gene}}
| caption =
| image =
| width =
| HGNCid = 10597
| Symbol = SCN9A
| AltSymbols = Nav1.7
| EntrezGene = 6335
| OMIM = 603415
| RefSeq = NM_002977
| UniProt = Q15858
| PDB =
| ECnumber =
| Chromosome = 2
| Arm = q
| Band = 24
| LocusSupplementaryData =
}}


'''Na<sub>v</sub>1.7''' is a [[sodium ion channel]] that in humans is encoded by the ''SCN9A'' gene.<ref name="pmid7720699">{{cite journal | vauthors = Klugbauer N, Lacinova L, Flockerzi V, Hofmann F | title = Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells | journal = The EMBO Journal | volume = 14 | issue = 6 | pages = 1084–90 | date = March 1995 | pmid = 7720699 | pmc = 398185 | doi =  }}</ref><ref name="pmid10198179">{{cite journal | vauthors = Plummer NW, Meisler MH | title = Evolution and diversity of mammalian sodium channel genes | journal = Genomics | volume = 57 | issue = 2 | pages = 323–31 | date = April 1999 | pmid = 10198179 | doi = 10.1006/geno.1998.5735 }}</ref><ref name="pmid16382098">{{cite journal | vauthors = Catterall WA, Goldin AL, Waxman SG | title = International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 397–409 | date = December 2005 | pmid = 16382098 | doi = 10.1124/pr.57.4.4 }}</ref> It is usually expressed at high levels in two types of [[neuron]]s: the nociceptive (pain) neurons at [[dorsal root ganglion]] (DRG) and [[trigeminal ganglion]] and [[sympathetic ganglion]] neurons, which are part of the [[autonomic nervous system|autonomic]] (involuntary) nervous system.<ref name="pmid15302875">{{cite journal | vauthors = Raymond CK, Castle J, Garrett-Engele P, Armour CD, Kan Z, Tsinoremas N, Johnson JM | title = Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia | journal = The Journal of Biological Chemistry | volume = 279 | issue = 44 | pages = 46234–41 | date = October 2004 | pmid = 15302875 | doi = 10.1074/jbc.M406387200 }}</ref><ref name="pmid16702558">{{cite journal | vauthors = Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG | title = A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 21 | pages = 8245–50 | date = May 2006 | pmid = 16702558 | pmc = 1472458 | doi = 10.1073/pnas.0602813103 }}</ref>


The '''Nav1.7''' [[sodium ion channel]] protein is encoded by gene {{Gene|SCN9A}}.
== Function ==
Recent studies have associated a defect in SCN9A with [[congenital insensitivity to pain]].<ref>http://www.nature.com/nature/journal/v444/n7121/abs/nature05413.html PMID 17167479  (pending)</ref>
Na<sub>v</sub>1.7 is a [[Voltage-gated sodium channel#Voltage-gated|voltage-gated sodium channel]] and plays a critical role in the generation and conduction of [[action potential]]s and is thus important for electrical signaling by most excitable cells. Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific [[Threshold potential|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 Na<sub>v</sub>1.7 channel produces a rapidly activating and inactivating current which  is sensitive to the level of tetrodotoxin.<ref name="pmid11031246">{{cite journal | vauthors = Catterall WA | title = Structure and regulation of voltage-gated Ca2+ channels | journal = Annual Review of Cell and Developmental Biology | volume = 16 | issue =  | pages = 521–55 | year = 2000 | pmid = 11031246 | doi = 10.1146/annurev.cellbio.16.1.521 }}</ref> Na<sub>v</sub>1.7 is important in the early phases of neuronal [[electrogenesis]]. Na<sub>v</sub>1.7 activity consists of a slow transition of the channel into an inactive state when it is depolarized, even to a minor degree.<ref name="Cummins_1998">{{cite journal | vauthors = Cummins TR, Howe JR, Waxman SG | title = Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel | journal = The Journal of Neuroscience | volume = 18 | issue = 23 | pages = 9607–19 | date = December 1998 | pmid = 9822722 }}</ref> 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.<ref name="Cummins_1998" /> This brings neurons to a voltage that stimulate [[SCN10A|Na<sub>v</sub>1.8]], which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.<ref>{{cite journal | vauthors = Renganathan M, Cummins TR, Waxman SG | title = Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons | journal = Journal of Neurophysiology | volume = 86 | issue = 2 | pages = 629–40 | date = August 2001 | pmid = 11495938 | doi = 10.1152/jn.2001.86.2.629 }}</ref>


==References==
==Clinical significance==
<references/>


{{Ion channels}}
===Animal studies===
The critical role of Na<sub>v</sub>1.7 in [[nociception]] and [[pain]] was originally shown using [[Cre-Lox recombination]] tissue specific knockout mice. These [[transgenic]] mice specifically lack Na<sub>v</sub>1.7 in [[Nav1.8|Na<sub>v</sub>1.8]] 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.<ref name="pmid15314237">{{cite journal | vauthors = Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN | title = Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 34 | pages = 12706–11 | date = August 2004 | pmid = 15314237 | pmc = 515119 | doi = 10.1073/pnas.0404915101 }}</ref> However, the expression of Na<sub>v</sub>1.7 is not restricted to Na<sub>v</sub>1.8 positive DRG neurons. Further work examining the behavioural response of two other transgenic mouse strains; one lacking Na<sub>v</sub>1.7 in all DRG neurons and the other lacking Na<sub>v</sub>1.7 in all DRG neurons as well as all sympathetic neurons, has revealed distinct sets of modality specific peripheral neurons.<ref name="PMID 22531176">{{cite journal | vauthors = Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, Malcangio M, Wood JN | title = Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons | journal = Nature Communications | volume = 3 | issue = 4 | pages = 791–799 | date = April 2012 | pmid = 22531176 | pmc = 3337979 | doi = 10.1038/ncomms1795 }}</ref> Therefore, Na<sub>v</sub>1.7 expressed in Na<sub>v</sub>1.8 positive DRG neurons is critical for normal responses to acute mechanical and inflammatory pain assays. Whilst Na<sub>v</sub>1.7 expressed in Na<sub>v</sub>1.8 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.


{{WH}}
===Primary erythromelalgia===
{{WikiDoc Sources}}
Mutation in Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7 channel. Multiple studies have found  a dozen ''SCN9A'' mutations in multiple families as causing erythromelagia.<ref name="Dib-Hajj_2013">{{cite journal | vauthors = Dib-Hajj SD, Yang Y, Black JA, Waxman SG | title = The Na(V)1.7 sodium channel: from molecule to man | journal = Nature Reviews. Neuroscience | volume = 14 | issue = 1 | pages = 49–62 | date = January 2013 | pmid = 23232607 | doi = 10.1038/nrn3404 }}</ref><ref name="Tang_2015">{{cite journal | vauthors = Tang Z, Chen Z, Tang B, Jiang H | title = Primary erythromelalgia: a review | journal = Orphanet Journal of Rare Diseases | volume = 10 | issue =  | pages = 127 | date = September 2015 | pmid = 26419464 | pmc = 4589109 | doi = 10.1186/s13023-015-0347-1 }}</ref> All of the observed [[erythromelalgia]] mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Na<sub>v</sub>1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated.<ref name="pmid8056469">{{cite journal | vauthors = Drenth JP, Michiels JJ | title = Erythromelalgia and erythermalgia: diagnostic differentiation | journal = International Journal of Dermatology | volume = 33 | issue = 6 | pages = 393–7 | date = June 1994 | pmid = 8056469 | doi = 10.1111/j.1365-4362.1994.tb04037.x }}</ref> 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 [[dorsal root ganglion|DRG]] neurons expressing these mutant channels, thus causing extreme sensitivity to pain ([[hyperalgesia]]). While the expression of PE Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.8 channels, which are selectively expressed in addition to Na<sub>v</sub>1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Na<sub>v</sub>1.7 results in inactivation of the sodium channels results in reduced excitability.  Thus physiological interaction of Na<sub>v</sub>1.7 and Na<sub>v</sub>1.8 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.<ref name="pmid16702558"/>
Recent studies have associated a defect in ''SCN9A'' with [[congenital insensitivity to pain]].<ref name="Golshani_2014">{{cite journal | vauthors = Golshani AE, Kamdar AA, Spence SC, Beckmann NM | title = Congenital indifference to pain: an illustrated case report and literature review | journal = Journal of Radiology Case Reports | volume = 8 | issue = 8 | pages = 16–23 | date = August 2014 | pmid = 25426241 | pmc = 4242143 | doi = 10.3941/jrcr.v8i8.2194 }}</ref>
 
===Paroxysmal extreme pain disorder===
[[Paroxysmal extreme pain disorder]] (PEPD) is another rare, extreme pain disorder.<ref name="AllertonFox2013">{{cite book |vauthors=Allerton C, Fox D | title = Pain Therapeutics: Current and Future Treatment Paradigms | url = https://books.google.com/books?id=zUINAgAAQBAJ&pg=PA146 | year = 2013 | publisher = Royal Society of Chemistry | isbn = 978-1-84973-645-9 | pages = 146–148}}</ref><ref name="KewDavies2010">{{cite book |vauthors=Kew JN, Davies CH | title = Ion Channels: From Structure to Function | url = https://books.google.com/books?id=TAWdlOB-UUsC&pg=PA153 | year = 2010 | publisher = Oxford University Press | isbn = 978-0-19-929675-0 | pages = 153–154}}</ref> Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Na<sub>v</sub>1.7 channel.<ref name="AllertonFox2013" /><ref name="KewDavies2010" />
 
{{Expand section|date=July 2014}}
 
===Congenital 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,<ref>{{cite journal | vauthors = Peddareddygari LR, Oberoi K, Grewal RP | title = Congenital insensitivity to pain: a case report and review of the literature | journal = Case Reports in Neurological Medicine | volume = 2014 | pages = 141953 | date = 2014-09-18 | pmid = 25309764 | pmc = 4182687 | doi = 10.1155/2014/141953 }}</ref> and are often only diagnosed because of limping or lack of use of a [[limb (anatomy)|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 Na<sub>v</sub>1.7 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 Na<sub>v</sub>1.7 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.<ref name="Golshani_2014" />
 
===Clinical analgesics===
[[Local anesthetic]]s such as [[lidocaine]], but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.<ref name="MashourLydic2011">{{cite book |vauthors=Mashour GA, Lydic R | title = Neuroscientific Foundations of Anesthesiology | url = https://books.google.com/books?id=M0NpAgAAQBAJ&pg=PA154 | date = 7 September 2011 | publisher = Oxford University Press | isbn = 978-0-19-987546-7 | page = 154}}</ref><ref name="Chahine">{{cite book | author = Mohamed Chahine | title = Recent advances in voltage-gated sodium channels, their pharmacology and related diseases | url = https://books.google.com/books?id=1IL_Q7UyYE8C&pg=PA90 | publisher = Frontiers E-books | isbn = 978-2-88919-128-4 | page = 90}}</ref> Na<sub>v</sub>1.7, as well as [[Nav1.3|Na<sub>v</sub>1.3]], Na<sub>v</sub>1.8, and [[Nav1.9|Na<sub>v</sub>1.9]], are the specific channels that have been implicated in pain signaling.<ref name="MashourLydic2011" /><ref name="LamberthDinges2012">{{cite book |vauthors=Lamberth C, Dinges J | title = Bioactive Heterocyclic Compound Classes: Pharmaceuticals | url = https://books.google.com/books?id=zk0cIhG4lIwC&pg=PA127 | date = 9 August 2012 | publisher = John Wiley & Sons | isbn = 978-3-527-66448-1 | page = 127}}</ref> Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.<ref name="MashourLydic2011" /> In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain [[tricyclic antidepressant]]s, and of [[mexiletine]].<ref name="Cairns2009">{{cite book | author = Cairns BE | title = Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management | url = https://books.google.com/books?id=MTSvERxiCrIC&pg=PA66 | date = 1 September 2009 | publisher = John Wiley & Sons | isbn = 978-0-470-52221-9 | pages = 66–68}}</ref><ref name="JamesBerger2015">{{cite book| first1 = William D. | last1 = James | first2 = Timothy | last2 = Berger | first3 = Dirk | last3 = Elston | name-list-format = vanc |title=Andrews' Diseases of the Skin: Clinical Dermatology|url=https://books.google.com/books?id=Np6cCQAAQBAJ&pg=PA810|date=12 April 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-31969-0|pages=810–}}</ref>
 
===Itch===
Mutations of Na<sub>v</sub>1.7 have been linked to itching (pruritus),<ref name="Devigilia2014">{{cite news | url = http://www.sciencedirect.com/science/article/pii/S0304395914002267 | title = Paroxysmal itch caused by gain-of-function Nav1.7 mutation | author = Grazia Devigilia, Roberto Eleopraa, Tiziana Pierrob, Raffaella Lombardib, Sara Rinaldoa, Christian Lettieria, Catharina G. Faberc, Ingemar S.J. Merkiesc, d, Stephen G. Waxmane, Giuseppe Lauriab | date = September 2014 | journal = Pain}}</ref><ref name="Devigilia2014comment">{{cite news | title = An SCN9A variant, known to cause pain, is now found to cause itch | journal = Pain| url = http://www.rosslab.neurobio.pitt.edu/wp-content/themes/rosslab-theme/files/preview_rosslab_pain_2014.pdf}}</ref> and genetic knockouts of Na<sub>v</sub>1.7<ref name="Gingras2014">{{cite journal | vauthors = Gingras J, Smith S, Matson DJ, Johnson D, Nye K, Couture L, Feric E, Yin R, Moyer BD, Peterson ML, Rottman JB, Beiler RJ, Malmberg AB, McDonough SI | title = Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain | journal = PLOS One | volume = 9 | issue = 9 | pages = e105895 | date = 2014 | pmid = 25188265 | pmc = 4154897 | doi = 10.1371/journal.pone.0105895 }}</ref> and an antibody that inhibits Na<sub>v</sub>1.7 also appear to inhibit itching.<ref name="Lee2014">{{cite journal | vauthors = Lee JH, Park CK, Chen G, Han Q, Xie RG, Liu T, Ji RR, Lee SY | title = A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief | journal = Cell | volume = 157 | issue = 6 | pages = 1393–404 | date = June 2014 | pmid = 24856969 | pmc = 4098795 | doi = 10.1016/j.cell.2014.03.064 }}</ref><ref name="Lee2014MartzCommentary">{{cite news | first = Lauren | last = Martz | name-list-format = vanc | title = Nav-i-gating antibodies for pain | journal = SciBX | url = http://www.nature.com/scibx/journal/v7/n23/full/scibx.2014.662.html}}</ref><ref name="Lee2014pressRelease">{{cite news | title = One Molecule To Block Both Pain And Itch | author = Sheila Yong | date = May 22, 2014 | url = http://today.duke.edu/2014/05/painitch}}</ref>
 
===Future prospects===
As the Na<sub>v</sub>1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,<ref name="KewDavies2010" /> there has been immense interest in developing selective Na<sub>v</sub>1.7 channel blockers as potential novel analgesics.<ref name="AltmanFlockhart2012">{{cite book |vauthors=Altman RB, Flockhart D, Goldstein DB | title = Principles of Pharmacogenetics and Pharmacogenomics | url = https://books.google.com/books?id=7EAhAwAAQBAJ&pg=PA224 | date = 23 January 2012 | publisher = Cambridge University Press | isbn = 978-1-107-37747-9 | page = 224}}</ref> Since Na<sub>v</sub>1.7 is not present in heart tissue or the central nervous system, selective blockers of Na<sub>v</sub>1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Na<sub>v</sub>1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.<ref name="AltmanFlockhart2012" /><ref name="pmid17167466">{{cite journal | vauthors = Waxman SG | title = Neurobiology: a channel sets the gain on pain | journal = Nature | volume = 444 | issue = 7121 | pages = 831–2 | date = December 2006 | pmid = 17167466 | doi = 10.1038/444831a }}</ref><ref name="pmid17950472">{{cite journal | vauthors = Dib-Hajj SD, Cummins TR, Black JA, Waxman SG | title = From genes to pain: Na v 1.7 and human pain disorders | journal = Trends in Neurosciences | volume = 30 | issue = 11 | pages = 555–63 | date = November 2007 | pmid = 17950472 | doi = 10.1016/j.tins.2007.08.004 }}</ref>
 
A number of selective Na<sub>v</sub>1.7 (and/or Na<sub>v</sub>1.8) blockers are in clinical development, including [[funapide]] (TV-45070, XEN402), [[PF-05089771]], [[DSP-2230]], [[NKTR-171]], [[GDC-0276]], and [[RG7893]] (GDC-0287).<ref name="BagalChapman2014">{{cite journal | vauthors = Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA | title = Recent progress in sodium channel modulators for pain | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 16 | pages = 3690–9 | date = August 2014 | pmid = 25060923 | doi = 10.1016/j.bmcl.2014.06.038 }}</ref><ref name="Martz2014">{{cite journal | vauthors = Martz L | title = Nav-i-gating antibodies for pain | journal = Science-Business eXchange | volume = 7 | issue = 23 | year = 2014 | issn = 1945-3477 | doi = 10.1038/scibx.2014.662}}</ref><ref name="McMahonKoltzenburg2013">{{cite book |vauthors=McMahon S, Koltzenburg M, Tracey I, Turk DC | title = Wall & Melzack's Textbook of Pain: Expert Consult - Online | url = https://books.google.com/books?id=ok0_jIJ0w_wC&pg=PA508 | date = 1 March 2013 | publisher = Elsevier Health Sciences | isbn = 0-7020-5374-0 | page = 508}}</ref> [[Ralfinamide]] (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Na<sub>v</sub> channel blocker which is under development for the treatment of pain.<ref name="SimpsonMcArthur2012">{{cite book|vauthors=Simpson DM, McArthur JC, Dworkin RH |title=Neuropathic Pain: Mechanisms, Diagnosis and Treatment|url=https://books.google.com/books?id=1fF7pRxFzZUC&pg=PA40|date=21 June 2012|publisher=Oxford University Press|isbn=978-0-19-539470-2|pages=40–}}</ref>
 
Surprisingly, many potent Na<sub>v</sub>1.7 blockers have been found to be clinically effective but only relatively weak analgesics.<ref name="MinettPereira2015">{{cite journal | vauthors = Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, Mancini F, Iannetti GD, Bogdanov YD, Santana-Varela S, Millet Q, Baskozos G, MacAllister R, Cox JJ, Zhao J, Wood JN | title = Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7 | journal = Nature Communications | volume = 6 | pages = 8967 | date = December 2015 | pmid = 26634308 | pmc = 4686868 | doi = 10.1038/ncomms9967 }}</ref> Recently, it has been elucidated that congenital loss of Nav<sub>v</sub>1.7 results in a dramatic increase in the levels of [[endogenous]] [[enkephalin]]s, and it was found that blocking these [[opioid]]s with the [[opioid antagonist]] [[naloxone]] allowed for pain sensitivity both in Nav<sub>v</sub>1.7 null mice and in a woman with a defective Nav<sub>v</sub>1.7 gene and associated [[congenital insensitivity to pain]].<ref name="MinettPereira2015" />  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.<ref name="pmid28045073">{{cite journal | vauthors = Flinspach M, Xu Q, Piekarz AD, Fellows R, Hagan R, Gibbs A, Liu Y, Neff RA, Freedman J, Eckert WA, Zhou M, Bonesteel R, Pennington MW, Eddinger KA, Yaksh TL, Hunter M, Swanson RV, Wickenden AD | title = Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor | journal = Scientific Reports | volume = 7 | issue =  | pages = 39662 | date = January 2017 | pmid = 28045073 | pmc = 5206724 | doi = 10.1038/srep39662 }}</ref>{{Unreliable medical source|date=August 2017|sure=y}} It is possible that channel blockade is maximal only when the channel is inhibited in its closed state. It appears that complete inactivation of Na<sub>v</sub> 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 [Na<sub>v</sub> 1.7] antagonists had failed in regards to achieving the same degree of analgesia as congenital Na<sub>v</sub> 1.7 inactivity.<ref name="MinettPereira2015" /> The proposed mechanism also suggests that the analgesic effects of Na<sub>v</sub>1.7 blockers may be greatly potentiated by the co-administration of [[exogenous]] opioids or [[enkephalinase inhibitor]]s.<ref name="MinettPereira2015" /> Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.<ref name="MinettPereira2015" />
 
An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.<ref name="MinettPereira2015" />
 
== References ==
{{Reflist|32em}}
 
== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Emery EC, Luiz AP, Wood JN | title = Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief | journal = Expert Opinion on Therapeutic Targets | volume = 20 | issue = 8 | pages = 975–83 | date = August 2016 | pmid = 26941184 | pmc = 4950419 | doi = 10.1517/14728222.2016.1162295 }}
{{refend}}
 
== External links ==
* {{MeshName|SCN9A+protein,+human}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=etha  GeneReviews/NCBI/NIH/UW entry on SCN9A-Related Inherited Erythromelalgia]
 
{{Ion channels|g2}}
{{Channelergics}}
 
[[Category:Sodium channels]]

Latest revision as of 16:45, 4 August 2018

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Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[1][2][3] 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.[4][5]

Function

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.[6] 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.[7] 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.[7] 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.[8]

Clinical significance

Animal studies

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.[9] 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.[10] 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

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.[11][12] 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.[13] 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.[5] Recent studies have associated a defect in SCN9A with congenital insensitivity to pain.[14]

Paroxysmal extreme pain disorder

Paroxysmal extreme pain disorder (PEPD) is another rare, extreme pain disorder.[15][16] Like primary erythromelalgia, PEPD is similarly the result of a gain-of-function mutation in the gene encoding the Nav1.7 channel.[15][16]

Congenital 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,[17] 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.[14]

Clinical analgesics

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.[18][19] Nav1.7, as well as Nav1.3, Nav1.8, and Nav1.9, are the specific channels that have been implicated in pain signaling.[18][20] Thus, the blockade of these specific channels is likely to underlie the analgesia of local anesthetics and anticonvulsants such as phenytoin.[18] In addition, inhibition of these channels is also likely responsible for the analgesic efficacy of certain tricyclic antidepressants, and of mexiletine.[21][22]

Itch

Mutations of Nav1.7 have been linked to itching (pruritus),[23][24] and genetic knockouts of Nav1.7[25] and an antibody that inhibits Nav1.7 also appear to inhibit itching.[26][27][28]

Future prospects

As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[16] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[29] 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.[29][30][31]

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).[32][33][34] 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.[35]

Surprisingly, many potent Nav1.7 blockers have been found to be clinically effective but only relatively weak analgesics.[36] 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.[36] 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.[37][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.[36] 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.[36] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.[36]

An additional implication of the aforementioned findings is that congenital insensitivity to pain may be clinically treatable with opioid antagonists.[36]

References

  1. ↑ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F (March 1995). "Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells". The EMBO Journal. 14 (6): 1084–90. PMC 398185. PMID 7720699.
  2. ↑ Plummer NW, Meisler MH (April 1999). "Evolution and diversity of mammalian sodium channel genes". Genomics. 57 (2): 323–31. doi:10.1006/geno.1998.5735. PMID 10198179.
  3. ↑ Catterall WA, Goldin AL, Waxman SG (December 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID 16382098.
  4. ↑ Raymond CK, Castle J, Garrett-Engele P, Armour CD, Kan Z, Tsinoremas N, Johnson JM (October 2004). "Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia". The Journal of Biological Chemistry. 279 (44): 46234–41. doi:10.1074/jbc.M406387200. PMID 15302875.
  5. ↑ 5.0 5.1 Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (May 2006). "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (21): 8245–50. doi:10.1073/pnas.0602813103. PMC 1472458. PMID 16702558.
  6. ↑ Catterall WA (2000). "Structure and regulation of voltage-gated Ca2+ channels". Annual Review of Cell and Developmental Biology. 16: 521–55. doi:10.1146/annurev.cellbio.16.1.521. PMID 11031246.
  7. ↑ 7.0 7.1 Cummins TR, Howe JR, Waxman SG (December 1998). "Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel". The Journal of Neuroscience. 18 (23): 9607–19. PMID 9822722.
  8. ↑ Renganathan M, Cummins TR, Waxman SG (August 2001). "Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons". Journal of Neurophysiology. 86 (2): 629–40. doi:10.1152/jn.2001.86.2.629. PMID 11495938.
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  13. ↑ Drenth JP, Michiels JJ (June 1994). "Erythromelalgia and erythermalgia: diagnostic differentiation". International Journal of Dermatology. 33 (6): 393–7. doi:10.1111/j.1365-4362.1994.tb04037.x. PMID 8056469.
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  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, Mancini F, Iannetti GD, Bogdanov YD, Santana-Varela S, Millet Q, Baskozos G, MacAllister R, Cox JJ, Zhao J, Wood JN (December 2015). "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7". Nature Communications. 6: 8967. doi:10.1038/ncomms9967. PMC 4686868. PMID 26634308.
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Further reading

External links

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