Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of theaction potential in most excitable cells. Alpha subunits, such as SCN11A, mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex. Aberrant expression patterns or mutations of alpha subunits underlie a number of disorders. Each alpha subunit consists of 4 domains connected by 3 intracellular loops; each domain consists of 6 transmembrane segments and intra- and extracellular linkers.[9] The 4th transmembrane segment of each domain is the voltage-sensing region of the channel. Followingdepolarization of the cell, voltage-gated sodium channels become inactivated through a change in conformation in which the 4th segments in each domain move into the pore region in response to the highly positive voltage expressed at the peak of theaction potential. This effectively blocks the Na+ pore and prevents further influx of Na+, therefore preventing further depolarization. Similarly, when the cell reaches its minimum (most negative) voltage duringhyperpolarization, the 4th segments respond by moving outward, thus reopening the pore and allowing Na+ to flow into the cell.[10]
Nav1.9 is known to play a role innociception, having been linked to the perception of inflammatory,neuropathic,[7] and cold-related pain.[11] It does this primarily through its ability to lower thethreshold potential of the neuron, allowing for an increase inaction potential firing that leads to hyperexcitability of the neuron and increased pain perception. Because of this role in altering the threshold potential, Nav1.9 is considered a threshold channel.[12][13] Though most sodium channels are blocked bytetrodotoxin, Nav1.9 is tetrodotoxin-resistant due to the presence of serine on an extracellular linker that plays a role in the selectivity of the pore for Na+.[7] This property is found in similar channels, namelyNav1.8,[10] and has been associated with slower channel kinetics than the tetrodotoxin-sensitive sodium channels.[14] In Nav1.9, this is mostly associated with the slower speed at which channel inactivation occurs.[7]
BothNav1.8 and Nav1.9 have been shown to play a role inbone cancer associated pain using a rat model of bone cancer. Thedorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to haveup-regulation ofNav1.8 and Nav1.9mRNA expression as well as an increase in total number of these alpha subunits. These results suggest thattetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.[15]
The role of Nav1.9 in chronic inflammatory joint pain has been demonstrated in rat models of chronic inflammatory knee pain. Expression of Nav1.9 in theafferent neurons of thedorsal root ganglion was found to be elevated as many as four weeks after the onset of the inflammatory pain. These results indicated that this alpha subunit plays some role in the maintenance of chronic inflammatory pain.[16]
There are currently many knowngain-of-function mutations in the humanSCN11A gene that are associated with various pain abnormalities. The majority of these mutations lead to the experience of episodic pain, mainly in the joints of the extremities. In some of these mutants, the pain symptoms began in early childhood and diminished somewhat with age,[17][18][19] but some of the mutants were asymptomatic until later in adulthood.[20][21] Many of these conditions are also accompanied by gastrointestinal disturbances such as constipation and diarrhea.[17][20] Additionally, one gain-of-function mutation onSCN11A has been linked with a congenital inability to experience pain.[22]
The role of Nav1.9 in inflammatory and neuropathic pain has made it a potential drug target for pain relief. It is thought that a drug that targets Nav1.9 could be used to decrease pain effectively while avoiding the many side effects associated with other high-strengthanalgesics.[7] Topicalmenthol blocks bothNav1.8 and Nav1.9 channels in thedorsal root ganglion. Menthol inhibits action potentials by dampening the Na+ channel activity without affecting normal neural activity in the affected area.[23] Nav1.9 has also been proposed as a target to treatoxaliplatin induced cold-associated pain side effects.[11]
^Dib-Hajj SD, Tyrrell L, Waxman SG (2002). "Structure of the sodium channel gene SCN11A: evidence for intron-to-exon conversion model and implications for gene evolution".Molecular Neurobiology.26 (2–3):235–50.doi:10.1385/MN:26:2-3:235.PMID12428758.S2CID25472814.
^abcdeDib-Hajj SD, Black JA, Waxman SG (September 2015). "NaV1.9: a sodium channel linked to human pain".Nature Reviews. Neuroscience.16 (9):511–9.doi:10.1038/nrn3977.PMID26243570.S2CID21443820.
^abCatterall WA, Perez-Reyes E, Snutch TP, Striessnig J (December 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels".Pharmacological Reviews.57 (4):411–25.doi:10.1124/pr.57.4.5.PMID16382099.S2CID10386627.
^Qiu F, Jiang Y, Zhang H, Liu Y, Mi W (March 2012). "Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain".Neuroscience Letters.512 (2):61–6.doi:10.1016/j.neulet.2012.01.069.PMID22342308.S2CID23296316.
^Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS (July 2008). "Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain".European Journal of Pain.12 (5):564–72.doi:10.1016/j.ejpain.2007.09.001.PMID17950013.S2CID24952010.
^abHan C, Yang Y, Te Morsche RH, Drenth JP, Politei JM, Waxman SG, Dib-Hajj SD (March 2017). "Familial gain-of-function Nav1.9 mutation in a painful channelopathy".Journal of Neurology, Neurosurgery, and Psychiatry.88 (3):233–240.doi:10.1136/jnnp-2016-313804.PMID27503742.S2CID23143509.
^Han C, Yang Y, de Greef BT, Hoeijmakers JG, Gerrits MM, Verhamme C, Qu J, Lauria G, Merkies IS, Faber CG, Dib-Hajj SD, Waxman SG (June 2015). "The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy".Neuromolecular Medicine.17 (2):158–69.doi:10.1007/s12017-015-8347-9.PMID25791876.S2CID2018253.
^Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, Ebbinghaus M, Goral RO, Stödberg T, Hennings JC, Bergmann M, Altmüller J, Thiele H, Wetzel A, Nürnberg P, Timmerman V, De Jonghe P, Blum R, Schaible HG, Weis J, Heinemann SH, Hübner CA, Kurth I (November 2013). "A de novo gain-of-function mutation in SCN11A causes loss of pain perception".Nature Genetics.45 (11):1399–404.doi:10.1038/ng.2767.PMID24036948.S2CID6166683.
^Gaudioso C, Hao J, Martin-Eauclaire MF, Gabriac M, Delmas P (February 2012). "Menthol pain relief through cumulative inactivation of voltage-gated sodium channels".Pain.153 (2):473–84.doi:10.1016/j.pain.2011.11.014.PMID22172548.S2CID3297690.
Jeong SY, Goto J, Hashida H, Suzuki T, Ogata K, Masuda N, Hirai M, Isahara K, Uchiyama Y, Kanazawa I (January 2000). "Identification of a novel human voltage-gated sodium channel alpha subunit gene, SCN12A".Biochemical and Biophysical Research Communications.267 (1):262–70.doi:10.1006/bbrc.1999.1916.PMID10623608.
