Nav1.9

Last updated
SCN11A
Identifiers
Aliases SCN11A , FEPS3, HSAN7, NAV1.9, NaN, PN5, SCN12A, SNS-2, sodium voltage-gated channel alpha subunit 11
External IDs OMIM: 604385 MGI: 1345149 HomoloGene: 8041 GeneCards: SCN11A
Orthologs
SpeciesHumanMouse
Entrez

11280

24046

Ensembl

ENSG00000168356

ENSMUSG00000034115

UniProt

Q9UI33

Q9R053

RefSeq (mRNA)

NM_001287223
NM_014139
NM_001349253

NM_011887

RefSeq (protein)

NP_054858
NP_001336182

NP_036017

Location (UCSC) Chr 3: 38.85 – 39.05 Mb Chr 9: 119.58 – 119.65 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] 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, [5] [7] but is also found in intrinsic myenteric neurons. [8]

Contents

Function

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. [9] 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. [10]

Nav1.9 is known to play a role in nociception, having been linked to the perception of inflammatory, neuropathic, [7] and cold-related pain. [11] 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. [12] [13] 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+. [7] This property is found in similar channels, namely Nav1.8, [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]

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. [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 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. [16]

Clinical significance

Gain-of-function mutations

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, [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 on SCN11A has been linked with a congenital inability to experience pain. [22]

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. [7] 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. [23] Nav1.9 has also been proposed as a target to treat oxaliplatin induced cold-associated pain side effects. [11]

Related Research Articles

Congenital insensitivity to pain (CIP), also known as congenital analgesia, is one or more extraordinarily rare conditions in which a person cannot feel physical pain. The conditions described here are separate from the HSAN group of disorders, which have more specific signs and cause. Because feeling physical pain is vital for survival, CIP is an extremely dangerous condition. It is common for people with the condition to die in childhood due to injuries or illnesses going unnoticed. Burn injuries are among the more common injuries.

<span class="mw-page-title-main">Erythromelalgia</span> Medical condition

Erythromelalgia or Mitchell's disease is a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked, then become hyperemic and inflamed. There is severe burning pain and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder. Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocytosis, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A.

Hyperkalemic periodic paralysis is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood. GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravet's syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.

Na<sub>v</sub>1.4 Protein-coding gene in the species Homo sapiens

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

SCN5A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

Na<sub>v</sub>1.7 Protein-coding gene in the species Homo sapiens

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 (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

Paralytic is a gene in the fruit fly, Drosophila melanogaster, which encodes a voltage gated sodium channel within D. melanogaster neurons. This gene is essential for locomotive activity in the fly. There are 9 different para alleles, composed of a minimum of 26 exons within over 78kb of genomic DNA. The para gene undergoes alternative splicing to produce subtypes of the channel protein. Flies with mutant forms of paralytic are used in fly models of seizures, since seizures can be easily induced in these flies.

SCN1A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

SCN2A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 2 subunit alpha, is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain sodium channel protein type 2 subunit alpha are sometimes called Nav1.2 channels.

<span class="mw-page-title-main">SCN3B</span> Protein-coding gene in the species Homo sapiens

Sodium channel subunit beta-3 is a protein that in humans is encoded by the SCN3B gene. Two alternatively spliced variants, encoding the same protein, have been identified.

<span class="mw-page-title-main">SCN1B</span> Protein-coding gene in the species Homo sapiens

Sodium channel subunit beta-1 is a protein that in humans is encoded by the SCN1B gene.

<span class="mw-page-title-main">SCN3A</span> Protein-coding gene in humans

Sodium channel, voltage-gated, type III, alpha subunit (SCN3A) is a protein that in humans is encoded by the SCN3A gene.

<span class="mw-page-title-main">SCN8A</span> Protein-coding gene in the species Homo sapiens

Sodium channel protein type 8 subunit alpha also known as Nav1.6 is a membrane protein encoded by the SCN8A gene. Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at each node of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.

<span class="mw-page-title-main">SCN7A</span> Protein-coding gene in the species Homo sapiens

Sodium channel protein type 7 subunit alpha is a protein that in humans is encoded by the SCN7A gene on the chromosome specifically located at 2q21-23 chromosome site. This is one of 10 Sodium channel types, and is expressed in the heart, the uterus and in glial cells. Its sequence identity is 48, and it is the only sodium channel known to be completely un-blockable by tetrodotoxin (TTX).

Na<sub>v</sub>1.8 Protein-coding gene in the species Homo sapiens

Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.

<span class="mw-page-title-main">Neosaxitoxin</span> Chemical compound

Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives.

<span class="mw-page-title-main">Stephen Waxman</span> American neurologist and neuroscientist

Stephen George Waxman is an American neurologist and neuroscientist. He served as Chairman of the Department of Neurology at Yale School of Medicine, and Neurologist-in-Chief at Yale-New Haven Hospital from 1986 until 2009. As of 2018, he is the Bridget Flaherty Professor of Neurology, Neurobiology, and Pharmacology at Yale University. He founded the Yale University Neuroscience & Regeneration Research Center in 1988 and is its Director. He previously held faculty positions at Harvard Medical School, MIT, and Stanford Medical School. He is also visiting professor at University College London. He is the editor-in-chief of The Neuroscientist and Neuroscience Letters.

μ-THTX-Cl6a, also known as Cl6a, is a 33-residue peptide toxin extracted from the venom of the spider Cyriopagopus longipes. The toxin acts as an inhibitor of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (NaV1.7), thereby causing sustained reduction of NaV1.7 currents.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000168356 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034115 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 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. S2CID   31355847.
  6. ↑ 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. S2CID   25472814.
  7. 1 2 3 4 5 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. S2CID   21443820.
  8. ↑ 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. doi: 10.1523/JNEUROSCI.23-07-02715.2003 . PMC   6742082 . PMID   12684457.
  9. ↑ "Entrez Gene: Sodium channel, voltage-gated, type XI, alpha subunit".
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  11. 1 2 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.
  12. ↑ 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.
  13. ↑ 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. S2CID   8541202.
  14. ↑ Yoshida S (June 1994). "Tetrodotoxin-resistant sodium channels". Cellular and Molecular Neurobiology. 14 (3): 227–44. doi:10.1007/bf02088322. PMID   7712513. S2CID   23386341.
  15. ↑ 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. S2CID   23296316.
  16. ↑ 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. S2CID   24952010.
  17. 1 2 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. S2CID   23143509.
  18. ↑ 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.
  19. ↑ 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. Bibcode:2015NatCo...610049L. doi:10.1038/ncomms10049. PMC   4686659 . PMID   26645915.
  20. 1 2 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.
  21. ↑ 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. S2CID   2018253.
  22. ↑ 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. S2CID   6166683.
  23. ↑ 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. S2CID   3297690.

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