Nav1.8

SCN10A
Identifiers
AliasesSCN10A, FEPS2, Nav1.8, PN3, SNS, hPN3, sodium voltage-gated channel alpha subunit 10
External IDsMGI: 108029 HomoloGene: 21300 GeneCards: SCN10A
Gene location (Human)
Chr.Chromosome 3 (human)[1]
BandNo data availableStart38,696,802 bp[1]
End38,794,010 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

6336

20264

Ensembl

ENSG00000185313

ENSMUSG00000034533

UniProt

Q9Y5Y9

Q6QIY3

RefSeq (mRNA)

NM_001293306
NM_001293307
NM_006514

NM_001205321
NM_009134

RefSeq (protein)

NP_001280235
NP_001280236
NP_006505

NP_001192250
NP_033160

Location (UCSC)Chr 3: 38.7 – 38.79 MbChr 3: 119.61 – 119.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nav1.8 is a sodium ion channel subunit that in humans is encoded by the SCN10A gene.[5][6][7][8]

Nav1.8-containing channels are tetrodotoxin (TTX)-resistant voltage-gated channels. Nav1.8 is expressed specifically in the dorsal root ganglion (DRG), in unmyelinated, small-diameter sensory neurons called C-fibres, and is involved in nociception.[9][10] C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain messages.

The specific location of Nav1.8 in sensory neurons of the DRG may make it a key therapeutic target for the development of new analgesics[11] and the treatment of chronic pain.[12]

Function

Voltage-gated sodium ion channels (VGSC) are essential in producing and propagating action potentials. Tetrodotoxin, a toxin found in pufferfish, is able to block some VGSCs and therefore is used to distinguish the different subtypes. There are three TTX-resistant VGSC: Nav1.5, Nav1.8 and Nav1.9. Nav1.8 and Nav1.9 are both expressed in nociceptors (damage-sensing neurons). Nav1.7, Nav1.8 and Nav1.9 are found in the DRG and help mediate chronic inflammatory pain.[13] Nav1.8 is an α-type channel subunit consisting of four homologous domains, each with six transmembrane regions, of which one is a voltage sensor.

Alpha subunit shown with four homologous domains each with six transmembrane spanning regions. The N-terminal and C-terminal are intracellular. Phosphorylation sites are shown for protein kinase A
Structure of Nav1.8, an α-type subunit with four homologous domains, each with six transmembrane regions. Each domain has a voltage sensor (purple). The 'P' represents the phosphorylation sites of Protein kinase A; N and C indicate the amino and carboxy termini of the protein chain. This image has been adapted from 'The trafficking of Nav1.8' [12]

Voltage clamp methods have been used to show how action potentials in DRG cells are shaped by TTX-resistant sodium channels. Nav1.8 contributes the most to sustaining the depolarising stage of action potentials in nociceptive sensory neurons because it activates quickly and remaining activated after detecting a noxious stimulus.[14][15] Therefore, Nav1.8 contributes to hyperalgesia (increased sensitivity to pain) and allodynia (pain from stimuli that do not usually cause it), which are elements of chronic pain.[16] Nav1.8 knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain.[9][17][18] Moreover, Nav1.8 plays a crucial role in cold pain.[19] Reducing the temperature from 30 °C to 10 °C slows the activation of VGSCs and hence decreases the current. However, Nav1.8 is cold-resistant and is able to generate action potentials in the cold to carry information from nociceptors to the central nervous system (CNS). Furthermore, Nav1.8-null mice failed to produce action potentials, indicating that Nav1.8 is essential to the perception of pain in cold temperatures.[19]

Clinical significance

Pain signalling pathways

Nociceptors are different from other sensory neurons in that they have a low activating threshold and consequently increase their response to constant stimuli. Therefore, nociceptors are easily sensitised by agents such as bradykinin and nerve growth factor, which are released at the site of tissue injury, ultimately causing changes to ion channel conductance. VGSCs have been shown to increase in density after nerve injury.[20] Therefore, VGSCs can be modulated by many different hyperalgesic agents that are released after nerve injury. Further examples include prostaglandin E2 (PGE2), serotonin and adenosine, which all act to increase the current through Nav1.8.[21]

Prostaglandins such as PGE2 can sensitise nociceptors to thermal, chemical and mechanical stimuli and increase the excitability of DRG sensory neurons. This occurs because PGE2 modulates the trafficking of Nav1.8 by binding to G-protein-coupled EP2 receptor, which in turn activates protein kinase A.[22][23] Protein kinase A phosphorylates Nav1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE2 and hyperalgesia comes from an antisense deoxynucleotide knockdown of Nav1.8 in the DRG of rats.[24] Another modulator of Nav1.8 is the ε isoform of PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Nav1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.[25]

Brugada syndrome

Mutations in SCN10A are associated to Brugada syndrome .[26]

Membrane trafficking

Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia).[27] The increased levels of nerve growth factor and tumour necrosis factor-α (TNF-α) causes the upregulation of Nav1.8 in sensory neurons via the accessory protein p11 (annexin II light chain). It has been shown using the yeast-two hybrid screening method that p11 binds to a 28-amino-acid fragment at the N terminus of Nav1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.[28] p11-null nociceptive sensory neurons in mice, created using the Cre-loxP recombinase system, show a decrease in Nav1.8 expression at the plasma membrane.[29] Therefore, disrupting the interactions between p11 and Nav1.8 may be a good therapeutic target for lowering pain.

In myelinated fibres, VGSCs are located at the nodes of Ranvier; however, in unmyelinated fibres, the exact location of VGSCs has not been determined. Nav1.8 in unmyelinated fibres has been found in clusters associated with lipid rafts along DRG fibers both in vitro and in vivo.[30] Lipid rafts organise the cell membrane, which includes trafficking and localising ion channels. Removal of lipid rafts in the membrane using MβCD, which depletes cholesterol from the plasma membrane, leads to a shift of Nav1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.[30]

Painful peripheral neuropathies

Painful peripheral neuropathies or small-fibre neuropathies are disorders of unmyelinated nociceptive C-fibres causing neuropathic pain; in some cases there is no known cause.[31] Genetic screening of patients with these idiopathic neuropathies has uncovered mutations in the SCN9A gene, encoding the related channel Nav1.7. A gain-of-function mutation in Nav1.7 located in the DRG sensory neurons was found in 30% of patients.[32] This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons and thus an increase in pain. Nav1.7 thus been shown to be linked to human pain; Nav1.8, by contrast, had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Nav1.8-encoding SCN10A gene in patients with painful peripheral neuropathy.[33] A study of 104 patients with idiopathic peripheral neuropathies who did not have the mutation in SCN9A used voltage clamp and current clamp methods, along with predictive algorithms, and yielded two gain-of-function mutations in SCN10A in three patients. Both mutations cause increased excitability in DRG sensory neurons and hence contribute to pain, but the mechanism by which they do so is not understood.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000185313 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034533 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ "Entrez Gene: sodium channel".
  6. ↑ Rabert DK, Koch BD, Ilnicka M, Obernolte RA, Naylor SL, Herman RC, Eglen RM, Hunter JC, Sangameswaran L (November 1998). "A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A". Pain. 78 (2): 107–14. PMID 9839820. doi:10.1016/S0304-3959(98)00120-1.
  7. ↑ Plummer NW, Meisler MH (April 1999). "Evolution and diversity of mammalian sodium channel genes". Genomics. 57 (2): 323–31. PMID 10198179. doi:10.1006/geno.1998.5735.
  8. ↑ 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. PMID 16382098. doi:10.1124/pr.57.4.4.
  9. 1 2 Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN (June 1999). "The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways". Nature Neuroscience. 2 (6): 541–8. PMID 10448219. doi:10.1038/9195.
  10. ↑ Akopian AN, Sivilotti L & Wood JN (January 1996). "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons". Nature. 379 (6562): 257–62. PMID 8538791. doi:10.1038/379257a0.
  11. ↑ Cummins TR, Sheets PL, Waxman SG (October 2007). "The roles of sodium channels in nociception: Implications for mechanisms of pain". Pain. 131 (3): 243–57. PMC 2055547 Freely accessible. PMID 17766042. doi:10.1016/j.pain.2007.07.026.
  12. 1 2 Swanwick RS, Pristerá A & Okuse K (December 2010). "The trafficking of Na(V)1.8". Neuroscience Letters. 486 (2): 78–83. PMC 2977848 Freely accessible. PMID 20816723. doi:10.1016/j.neulet.2010.08.074.
  13. ↑ 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. PMID 17950013. doi:10.1016/j.ejpain.2007.09.001.
  14. ↑ Blair NT & Bean BP (2002). "Roles of Tetrodotoxin (TTX)-Sensitive Na+ Current, TTX-Resistant Na+ Current, and Ca2+ Current in the Action Potentials of Nociceptive Sensory Neurons". The Journal of Neuroscience. 22 (23): 10277–10290. PMID 12451128.
  15. ↑ Renganathan M, Cummins TR & Waxman SG (2001). "Contribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons". Journal of Neurophysiology. 86 (2): 629–640. PMID 11495938.
  16. ↑ Millan MJ (1999). "The induction of pain: an integrative review". Progress in Neurobiology. 57: 1–164. doi:10.1016/S0301-0082(98)00048-3.
  17. ↑ Matthews EA, Wood JN & Dickenson AH (February 2006). "Na(v) 1.8-null mice show stimulus-dependent deficits in spinal neuronal activity". Molecular Pain. 2: 5. PMC 1403745 Freely accessible. PMID 16478543. doi:10.1186/1744-8069-2-5.
  18. ↑ Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS (May 2007). "A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat". Proceedings of the National Academy of Sciences of the United States of America. 104 (20): 8520–5. PMC 1895982 Freely accessible. PMID 17483457. doi:10.1073/pnas.0611364104.
  19. 1 2 Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW (June 2007). "Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures". Nature. 447 (7146): 855–8. PMID 17568746. doi:10.1038/nature05880.
  20. ↑ Devor M; Govrin-Lippmann R & Angelides (1993). "Na+ Channel lmmunolocalization in Peripheral Mammalian Axons and Changes following Nerve Injury and Neuroma Formation". The Journal of Neuroscience. 13 (5): 1976–1992. PMID 7683047.
  21. ↑ Toyo-Oka T, Masaki T (August 1979). "Calcium-activated neutral protease from bovine ventricular muscle: isolation and some of its properties". Journal of Molecular and Cellular Cardiology. 11 (8): 769–86. PMC 40039 Freely accessible. PMID 8577723. doi:10.1073/pnas.93.3.1108.
  22. ↑ England S, Bevan S & Docherty RJ (1996). "PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade". The Journal of Physiology. 1: 429–440. doi:10.1113/jphysiol.1996.sp021604.
  23. ↑ Liu C, Li Q, Su Y & Bao L (March 2010). "Prostaglandin E2 promotes Na1.8 trafficking via its intracellular RRR motif through the protein kinase A pathway". Traffic. 11 (3): 405–17. PMID 20028484. doi:10.1111/j.1600-0854.2009.01027.x.
  24. ↑ Khasar SG, Gold MS & Levine JD (1998). "A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat". Neuroscience Letters. 256 (1): 17–20. PMID 9832206. doi:10.1016/s0304-3940(98)00738-1.
  25. ↑ Wu DF, Chandra D, McMahon T, Wang D, Dadgar J, Kharazia VN, Liang YJ, Waxman SG, Dib-Hajj SD, Messing RO (April 2012). "PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice". The Journal of Clinical Investigation. 122 (4): 1306–15. PMC 3315445 Freely accessible. PMID 22426212. doi:10.1172/JCI61934.
  26. ↑ Hu D, Barajas-Martínez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, Betzenhauser MJ, Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P, Marieb M, Nam GB, Bhatia A, Hasdemir C, Haïssaguerre M, Veltmann C, Schimpf R, Borggrefe M, Viskin S, Antzelevitch C (July 2014). "Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome". Journal of the American College of Cardiology. 64 (1): 66–79. PMC 4116276 Freely accessible. PMID 24998131. doi:10.1016/j.jacc.2014.04.032.
  27. ↑ McMahon SB (March 1996). "NGF as a mediator of inflammatory pain". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 351 (1338): 431–40. PMID 8730782. doi:10.1098/rstb.1996.0039.
  28. ↑ Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV, Wood JN (June 2002). "Annexin II light chain regulates sensory neuron-specific sodium channel expression". Nature. 417 (6889): 653–6. PMID 12050667. doi:10.1038/nature00781.
  29. ↑ Foulkes T, Nassar MA, Lane T, Matthews EA, Baker MD, Gerke V, Okuse K, Dickenson AH, Wood JN (October 2006). "Deletion of annexin 2 light chain p11 in nociceptors causes deficits in somatosensory coding and pain behavior". The Journal of Neuroscience. 26 (41): 10499–507. PMID 17035534. doi:10.1523/JNEUROSCI.1997-06.2006.
  30. 1 2 Pristerà A, Baker MD & Okuse K (2012). "Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability". PloS One. 7 (8): e40079. PMC 3411591 Freely accessible. PMID 22870192. doi:10.1371/journal.pone.0040079.
  31. ↑ Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG (May 2012). "Small-fibre neuropathies--advances in diagnosis, pathophysiology and management". Nature Reviews. Neurology. 8 (7): 369–79. PMID 22641108. doi:10.1038/nrneurol.2012.97.
  32. ↑ Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS (January 2012). "Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy". Annals of Neurology. 71 (1): 26–39. PMID 21698661. doi:10.1002/ana.22485.
  33. ↑ Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG (November 2012). "Gain-of-function Nav1.8 mutations in painful neuropathy". Proceedings of the National Academy of Sciences of the United States of America. 109 (47): 19444–9. PMC 3511073 Freely accessible. PMID 23115331. doi:10.1073/pnas.1216080109.

Further reading

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.