Na_v1.8

Na_v1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.[5][6][7][8]

SCN10A
Identifiers
Aliases	SCN10A, FEPS2, Nav1.8, PN3, SNS, hPN3, sodium voltage-gated channel alpha subunit 10
External IDs	OMIM: 604427 MGI: 108029 HomoloGene: 21300 GeneCards: SCN10A
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p22.2 Start 38,696,802 bp[1] End 38,816,286 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F3|9 71.33 cM Start 119,608,456 bp[2] End 119,719,322 bp[2]
Gene ontology Molecular function • voltage-gated sodium channel activity • ion channel activity • ion channel binding • sodium channel activity • voltage-gated ion channel activity Cellular component • integral component of membrane • voltage-gated sodium channel complex • membrane • clathrin complex • extracellular exosome • cell membrane • axon • glutamatergic synapse • integral component of presynaptic membrane Biological process • bundle of His cell action potential • sodium ion transmembrane transport • transmembrane transport • neuronal action potential • regulation of heart rate • regulation of atrial cardiac muscle cell membrane depolarization • membrane depolarization during action potential • nociception • regulation of ion transmembrane transport • ion transport • regulation of cardiac muscle contraction • AV node cell action potential • sodium ion transport • odontogenesis of dentin-containing tooth • sensory perception • postsynaptic potential • transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
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 – 38.82 Mb	Chr 9: 119.61 – 119.72 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Na_v1.8-containing channels are tetrodotoxin (TTX)-resistant voltage-gated channels. Na_v1.8 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 Na_v1.8 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: Na_v1.5, Na_v1.8 and Na_v1.9. Na_v1.8 and Na_v1.9 are both expressed in nociceptors (damage-sensing neurons). Na_v1.7, Na_v1.8 and Na_v1.9 are found in the DRG and help mediate chronic inflammatory pain.[13] Na_v1.8 is an α-type channel subunit consisting of four homologous domains, each with six transmembrane regions, of which one is a voltage sensor.

Structure of Na_v1.8, 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 Na_v1.8'[12]

Voltage clamp methods have demonstrated that Na_V1.8 is unique, among sodium channels, in exhibiting relatively depolarized steady-state inactivation. Thus, Na_V1.8 remains available to operate, when neurons are depolarized to levels that inactivate other sodium channels. Voltage clamp has been used to show how action potentials in DRG cells are shaped by TTX-resistant sodium channels. Na_v1.8 contributes the most to sustaining the depolarizing stage of action repetitive high-frequency potentials in nociceptive sensory neurons because it activates quickly and remaining activated after detecting a noxious stimulus.[14][15] Therefore, Na_v1.8 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] Na_v1.8 knockout mice studies have shown that the channel is associated with inflammatory and neuropathic pain.[9][17][18] Moreover, Na_v1.8 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, Na_v1.8 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, Na_v1.8-null mice failed to produce action potentials, indicating that Na_v1.8 is essential to the perception of pain in cold temperatures.[19]

Although the early studies on the biophysics of Na_V1.8 channels were carried out in rodent channels, more recent studies have examined the properties of human Na_V1.8 channels. Notably, human Na_V1.8 channels exhibit an inactivation voltage-dependence that is even more depolarized than that in rodents, and it also exhibits a larger persistent current.[20] Thus, the influence of human Na_V1.8 channels on firing of sensory neurons may be even larger than that of rodent Na_V1.8 channels.

Gain-of-function mutations of Na_V1.8, identified in patients with painful peripheral neuropathies, have been found to make DRG neurons hyper excitable, and thus are causes of pain.[21][22] Although Na_V1.8 is not normally expressed within the cerebellum, its expression is up-regulated in cerebellar Purkinje cells in animal models of MS (Multiple Sclerosis), and in human MS.[23] The presence of Na_V1.8 channels within these cerebellar neurons, where it is not normally present, increases their excitability and alters their firing pattern in vitro,[24] and in rodents with experimental autoimmune encephalomyelitis, a model of MS.[25] At a behavioral level, the ectopic expression of Na_V1.8 within cerebellar Purkinje neurons has been shown to impair motor performance in a transgenic model.[26]

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.[27] 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 Na_v1.8.[28]

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 Na_v1.8 by binding to G-protein-coupled EP2 receptor, which in turn activates protein kinase A.[29][30] Protein kinase A phosphorylates Na_v1.8 at intracellular sites, resulting in increased sodium ion currents. Evidence for a link between PGE₂ and hyperalgesia comes from an antisense deoxynucleotide knockdown of Na_v1.8 in the DRG of rats.[31] Another modulator of Na_v1.8 is the ε isoform of PKC. This isoform is activated by the inflammatory mediator bradykinin and phosphorylates Na_v1.8, causing an increase in sodium current in the sensory neurons, which promotes mechanical hyperalgesia.[32]

Brugada syndrome

Mutations in SCN10A are associated to Brugada syndrome.[33]

Membrane trafficking

Nerve growth factor levels in inflamed or injured tissues are increased creating an increased sensitivity to pain (hyperalgesia).[34] The increased levels of nerve growth factor and tumour necrosis factor-α (TNF-α) causes the upregulation of Na_v1.8 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 Na_v1.8 and promotes its translocation to the plasma membrane. This contributes to the hyperexcitability of sensory neurons during pain.[35] p11-null nociceptive sensory neurons in mice, created using the Cre-loxP recombinase system, show a decrease in Na_v1.8 expression at the plasma membrane.[36] Therefore, disrupting the interactions between p11 and Na_v1.8 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. Na_v1.8 in unmyelinated fibres has been found in clusters associated with lipid rafts along DRG fibers both in vitro and in vivo.[37] 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 Na_v1.8 to a non-raft portion of the membrane, causing reduced action potential firing and propagation.[37]

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.[38] Genetic screening of patients with these idiopathic neuropathies has uncovered mutations in the SCN9A gene, encoding the related channel Na_v1.7. A gain-of-function mutation in Na_v1.7 located in the DRG sensory neurons was found in 30% of patients.[39] This gain-of-function mutation causes an increase in excitability (hyperexcitability) of DRG sensory neurons and thus an increase in pain. Na_v1.7 thus been shown to be linked to human pain; Na_v1.8, by contrast, had only been associated to pain in animal studies until recently. A gain-of-function mutation was found in the Na_v1.8-encoding SCN10A gene in patients with painful peripheral neuropathy.[21] 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

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Further reading

• Okuse K (2007). "Pain signalling pathways: from cytokines to ion channels". The International Journal of Biochemistry & Cell Biology. 39 (3): 490–6. doi:10.1016/j.biocel.2006.11.016. PMID 17194618.
• Waxman SG (July 2013). "Painful Na-channelopathies: an expanding universe". Trends in Molecular Medicine. 19 (7): 406–9. doi:10.1016/j.molmed.2013.04.003. PMID 23664154.
• Lai J, Porreca F, Hunter JC, Gold MS (2004). "Voltage-gated sodium channels and hyperalgesia". Annual Review of Pharmacology and Toxicology. 44: 371–97. doi:10.1146/annurev.pharmtox.44.101802.121627. PMID 14744251.
• Wood JN, Boorman JP, Okuse K, Baker MD (October 2004). "Voltage-gated sodium channels and pain pathways". Journal of Neurobiology. 61 (1): 55–71. doi:10.1002/neu.20094. PMID 15362153.
• Malik-Hall M, Poon WY, Baker MD, Wood JN, Okuse K (February 2003). "Sensory neuron proteins interact with the intracellular domains of sodium channel NaV1.8". Brain Research. Molecular Brain Research. 110 (2): 298–304. doi:10.1016/S0169-328X(02)00661-7. PMID 12591166.
• Yamaoka K, Inoue M, Miyazaki K, Hirama M, Kondo C, Kinoshita E, Miyoshi H, Seyama I (March 2009). "Synthetic ciguatoxins selectively activate Nav1.8-derived chimeric sodium channels expressed in HEK293 cells". The Journal of Biological Chemistry. 284 (12): 7597–605. doi:10.1074/jbc.M806481200. PMC 2658054. PMID 19164297.
• Choi JS, Hudmon A, Waxman SG, Dib-Hajj SD (July 2006). "Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons". Journal of Neurophysiology. 96 (1): 97–108. doi:10.1152/jn.00854.2005. PMID 16598065.
• Liu CJ, Priest BT, Bugianesi RM, Dulski PM, Felix JP, Dick IE, Brochu RM, Knaus HG, Middleton RE, Kaczorowski GJ, Slaughter RS, Garcia ML, Köhler MG (February 2006). "A high-capacity membrane potential FRET-based assay for NaV1.8 channels". Assay and Drug Development Technologies. 4 (1): 37–48. doi:10.1089/adt.2006.4.37. PMID 16506887.
• Browne LE, Blaney FE, Yusaf SP, Clare JJ, Wray D (April 2009). "Structural determinants of drugs acting on the Nav1.8 channel". The Journal of Biological Chemistry. 284 (16): 10523–36. doi:10.1074/jbc.M807569200. PMC 2667739. PMID 19233853.
• 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. doi:10.1016/S0304-3959(98)00120-1. PMID 9839820. S2CID 45480324.
• 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.
• 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. S2CID 7332624.

External links

• The London Pain Consortium