|, FEPS3, HSAN7, NAV1.9, NaN, PN5, SCN12A, SNS-2, sodium voltage-gated channel alpha subunit 11|
Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.
Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action 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. The 4th transmembrane segment of each domain is the voltage-sensing region of the channel. Following depolarization 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 the action 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 during hyperpolarization, the 4th segments respond by moving outward, thus reopening the pore and allowing Na+ to flow into the cell.
Nav1.9 is known to play a role in nociception, having been linked to the perception of inflammatory, neuropathic, and cold-related pain. It does this primarily through its ability to lower the threshold potential of the neuron, allowing for an increase in action 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. Though most sodium channels are blocked by tetrodotoxin, 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+. This property is found in similar channels, namely Nav1.8, and has been associated with slower channel kinetics than the tetrodotoxin-sensitive sodium channels. In Nav1.9, this is mostly associated with the slower speed at which channel inactivation occurs.
Animal models of pain
Both Nav1.8 and Nav1.9 have been shown to play a role in bone cancer associated pain using a rat model of bone cancer. The dorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to have up-regulation of Nav1.8 and Nav1.9 mRNA expression as well as an increase in total number of these alpha subunits. These results suggest that tetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.
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 the afferent neurons of the dorsal 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.
There are currently many known gain-of-function mutations in the human SCN11A 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, but some of the mutants were asymptomatic until later in adulthood. Many of these conditions are also accompanied by gastrointestinal disturbances such as constipation and diarrhea. Additionally, one gain-of-function mutation on SCN11A has been linked with a congenital inability to experience pain.
As a drug target for pain relief
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-strength analgesics. Topical menthol blocks both Nav1.8 and Nav1.9 channels in the dorsal root ganglion. Menthol inhibits action potentials by dampening the Na+ channel activity without affecting normal neural activity in the affected area. Nav1.9 has also been proposed as a target to treat oxaliplatin induced cold-associated pain side effects.
- GRCh38: Ensembl release 89: ENSG00000168356 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000034115 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Dib-Hajj S, Black JA, Cummins TR, Waxman SG (May 2002). "NaN/Nav1.9: a sodium channel with unique properties". Trends in Neurosciences. 25 (5): 253–9. doi:10.1016/S0166-2236(02)02150-1. PMID 11972962.
- 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. PMID 12428758.
- Dib-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. PMID 26243570.
- Rugiero F, Mistry M, Sage D, Black JA, Waxman SG, Crest M, Clerc N, Delmas P, Gola M (April 2003). "Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons". The Journal of Neuroscience. 23 (7): 2715–25. PMID 12684457.
- "Entrez Gene: Sodium channel, voltage-gated, type XI, alpha subunit".
- Catterall 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. PMID 16382099.
- Lolignier S, Bonnet C, Gaudioso C, Noël J, Ruel J, Amsalem M, Ferrier J, Rodat-Despoix L, Bouvier V, Aissouni Y, Prival L, Chapuy E, Padilla F, Eschalier A, Delmas P, Busserolles J (May 2015). "The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia". Cell Reports. 11 (7): 1067–78. doi:10.1016/j.celrep.2015.04.027. PMID 25959819.
- Baker MD, Chandra SY, Ding Y, Waxman SG, Wood JN (April 2003). "GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones". The Journal of Physiology. 548 (Pt 2): 373–82. doi:10.1111/j.1469-7793.2003.00373.x. PMC 2342858. PMID 12651922.
- Herzog RI, Cummins TR, Waxman SG (September 2001). "Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons". Journal of Neurophysiology. 86 (3): 1351–64. doi:10.1152/jn.2001.86.3.1351. PMID 11535682.
- Yoshida S (June 1994). "Tetrodotoxin-resistant sodium channels". Cellular and Molecular Neurobiology. 14 (3): 227–44. doi:10.1007/bf02088322. PMID 7712513.
- 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. PMID 22342308.
- 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. PMID 17950013.
- Han 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. PMID 27503742.
- Zhang XY, Wen J, Yang W, Wang C, Gao L, Zheng LH, Wang T, Ran K, Li Y, Li X, Xu M, Luo J, Feng S, Ma X, Ma H, Chai Z, Zhou Z, Yao J, Zhang X, Liu JY (November 2013). "Gain-of-function mutations in SCN11A cause familial episodic pain". American Journal of Human Genetics. 93 (5): 957–66. doi:10.1016/j.ajhg.2013.09.016. PMC 3824123. PMID 24207120.
- Leipold E, Hanson-Kahn A, Frick M, Gong P, Bernstein JA, Voigt M, Katona I, Oliver Goral R, Altmüller J, Nürnberg P, Weis J, Hübner CA, Heinemann SH, Kurth I (December 2015). "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant". Nature Communications. 6: 10049. doi:10.1038/ncomms10049. PMC 4686659. PMID 26645915.
- Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JG, Gerrits MM, Tyrrell L, Lauria G, Faber CG, Dib-Hajj SD, Merkies IS, Waxman SG (June 2014). "Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy". Brain. 137 (Pt 6): 1627–42. doi:10.1093/brain/awu079. PMID 24776970.
- 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. PMID 25791876.
- 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. PMID 24036948.
- 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. PMID 22172548.
- Delmas P, Coste B (February 2003). "Na+ channel Nav1.9: in search of a gating mechanism". Trends in Neurosciences. 26 (2): 55–7. doi:10.1016/S0166-2236(02)00030-9. PMID 12536125.
- Blum R, Kafitz KW, Konnerth A (October 2002). "Neurotrophin-evoked depolarization requires the sodium channel Na(V)1.9". Nature. 419 (6908): 687–93. doi:10.1038/nature01085. PMID 12384689.
- 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.
- Dib-Hajj SD, Tyrrell L, Escayg A, Wood PM, Meisler MH, Waxman SG (August 1999). "Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN". Genomics. 59 (3): 309–18. doi:10.1006/geno.1999.5890. PMID 10444332.
- Dib-Hajj SD, Tyrrell L, Cummins TR, Black JA, Wood PM, Waxman SG (November 1999). "Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons". FEBS Letters. 462 (1–2): 117–20. doi:10.1016/S0014-5793(99)01519-7. PMID 10580103.
- 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. PMID 10623608.
- Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB, Noda M, Tamkun MM, Waxman SG, Wood JN, Catterall WA (November 2000). "Nomenclature of voltage-gated sodium channels". Neuron. 28 (2): 365–8. doi:10.1016/S0896-6273(00)00116-1. PMID 11144347.
- 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.