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Gene Review

Scn10a  -  sodium channel, voltage-gated, type X, alpha

Mus musculus

Synonyms: Nav1.8, PN3, Peripheral nerve sodium channel 3, SNS, Sensory neuron sodium channel, ...
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Disease relevance of Scn10a

  • In recordings at approximately 22 days, a similar proportion of fibres were mechanosensitive in wild-type and Nav1.8 null neuromas (51 and 46%, respectively) [1].
  • In this study, we used sensory neuron specific (SNS) sodium channel gene knockout (-/-) mice to ask whether SNS sodium channel produces the slow Na(+) current ("slow") in large (>40 microm diam) cutaneous afferent dorsal root ganglion (DRG) neurons [2].
  • Together, these findings suggest that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na+ (Nav1.8) currents [3].
  • Using recombinant lambda phage clones encoding a mouse 129/SV genomic library, we have determined the detailed structure of the mouse SNS gene (Scn10a), including the location of exon-intron boundaries and the nucleotide sequence of the exons [4].
  • Here we compared visceral pain and referred hyperalgesia in Nav1.8-null mice and their wild-type littermates in five tests that differ in the degree to which behavior depends on spontaneous, ongoing firing in sensitized nociceptors [5].

Psychiatry related information on Scn10a

  • Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds [6].

High impact information on Scn10a

  • As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants [7].
  • We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease [8].
  • Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels [8].
  • Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis [8].
  • SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain [8].

Chemical compound and disease context of Scn10a

  • However, Nav1.8-null mutants showed weak pain and no referred hyperalgesia to intracolonic capsaicin, a model in which behavior is sustained by ongoing activity in nociceptors sensitized by the initial application [5].
  • To distinguish between a possible role for Nav1.8 in ongoing activity per se and ongoing activity after sensitization in the absence of additional stimuli, we tried a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis [5].
  • The low NE turnover in IBAT of MSG-treated mice prior to the onset of gross obesity suggests that low SNS activity may be an initial contributor to their high energy efficiency and resultant obesity [9].
  • To clarify whether hyperinsulinemia accelerates sympathetic nervous system (SNS) activity, norepinephrine (NE) turnover, a reliable indicator of SNS activity, was measured in the interscapular brown adipose tissue (IBAT) and heart of hyperinsulinemic yellow KK and normoinsulinemic C57BL control mice at 12 weeks of age [10].
  • We examined the impact of concurrent inhibition of RAS (captopril or losartan) and the SNS (prazosin) before and after acute nitric oxide (NO) synthase inhibition with L-nitro-L-arginine methyl ester (L-NAME) on renal cortical perfusion (RCF) and blood pressure (MAP) in healthy and acute ischemic renal failure (ARF) rats (n = 6) [11].

Biological context of Scn10a

  • Scn11a is located on mouse chromosome 9, close to the two other TTX-R sodium channel genes, Scn5a and Scn10a [12].
  • The tetrodotoxin-resistant sodium channel alpha subunit, Nav1.8, is exclusively expressed in primary sensory neurons and is suggested to play a role in the generation of ectopic action potentials after axonal injury and thereby contribute to neuropathic pain [1].
  • At approximately 10 days, neither genotype showed spontaneous activity, but a significantly higher proportion of fibres were mechanosensitive in wild-type (54%) compared to Nav1.8 null neuromas (18%) [1].
  • One current has physiological properties similar to those reported for SNS, while the other displays hyperpolarized voltage-dependence and persistent kinetics; a similar TTX-R current was recently identified in DRG neurons of sns-null mouse [13].
  • The sizes of the exons and the exon-intron junction positions of the mouse SNS and the human skeletal muscle VGSC genes are remarkably conserved [4].

Anatomical context of Scn10a

  • Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a [4].
  • Two voltage gated sodium channel alpha-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain [6].
  • Here we describe the generation of transgenic mouse lines which express Cre recombinase selectively in sensory ganglia using promoter elements of the Na(v)1.8 gene (Scn10a) [14].
  • To assess whether muscle-derived NT-3 could prevent injury-induced neuronal death, neuron survival in the DRG was analyzed in mice 5 days after sciatic nerve crush on PN3 [15].
  • Two tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels, SNS and NaN, are preferentially expressed in small dorsal root ganglia (DRG) and trigeminal ganglia neurons, most of which are nociceptive, of rat and mouse [13].

Associations of Scn10a with chemical compounds


Physical interactions of Scn10a

  • We show here that calmodulin coimmunoprecipitates with endogenous Nav1.8 channels from native DRG, suggesting that the two proteins can interact in vivo [20].

Regulatory relationships of Scn10a

  • Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons [20].

Other interactions of Scn10a

  • Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat [21].
  • Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse [22].
  • Thus SNS and NaN channels appear to produce different currents in human DRG neurons [13].
  • alpha-SNS produces the slow TTX-resistant sodium current in large cutaneous afferent DRG neurons [2].
  • Using whole-cell patch-clamp recording, we observed a greater than two-fold reduction of tetrodotoxin-resistant (TTX-R) Nav1.8 and Nav1.9 current densities in IB4+ DRG neurons cultured from CNTN-/- vs. CNTN+/+ mice [23].

Analytical, diagnostic and therapeutic context of Scn10a

  • These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects [24].
  • The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen-induced arthritis (CIA) [25].
  • Adrenalectomy reduced PNMT levels in the SNS and CNS, suggesting that the transgene is positively regulated by adrenal steroids [17].
  • Immunoblotting and RT-PCR assays showed reduced Nav1.8 levels in aged mice [26].
  • Unexpectedly, however, sympathectomy resulted in suppression of EAE in IL-4-/- mice, implying that control of actively induced EAE by the SNS depends on the genetic background of mice [27].


  1. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. Roza, C., Laird, J.M., Souslova, V., Wood, J.N., Cervero, F. J. Physiol. (Lond.) (2003) [Pubmed]
  2. alpha-SNS produces the slow TTX-resistant sodium current in large cutaneous afferent DRG neurons. Renganathan, M., Cummins, T.R., Hormuzdiar, W.N., Waxman, S.G. J. Neurophysiol. (2000) [Pubmed]
  3. Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability. Beyak, M.J., Ramji, N., Krol, K.M., Kawaja, M.D., Vanner, S.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  4. Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a. Souslova, V.A., Fox, M., Wood, J.N., Akopian, A.N. Genomics (1997) [Pubmed]
  5. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. Laird, J.M., Souslova, V., Wood, J.N., Cervero, F. J. Neurosci. (2002) [Pubmed]
  6. Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8. Nassar, M.A., Levato, A., Stirling, L.C., Wood, J.N. Molecular pain [electronic resource] (2005) [Pubmed]
  7. Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Lim, K.C., Lakshmanan, G., Crawford, S.E., Gu, Y., Grosveld, F., Engel, J.D. Nat. Genet. (2000) [Pubmed]
  8. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Black, J.A., Dib-Hajj, S., Baker, D., Newcombe, J., Cuzner, M.L., Waxman, S.G. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  9. Reduced norepinephrine turnover in brown adipose tissue of pre-obese mice treated with monosodium-L-glutamate. Yoshida, T., Nishioka, H., Nakamura, Y., Kanatsuna, T., Kondo, M. Life Sci. (1985) [Pubmed]
  10. Hyperinsulinemic yellow KK mice and norepinephrine turnover. Nishioka, H., Yoshida, T., Yoshioka, K., Kondo, M. Endocrinol. Jpn. (1987) [Pubmed]
  11. Interactions of the renin-angiotensin system and alpha-1 adrenoceptors on renal hemodynamics in healthy and acute renal failure rats: the role of nitric oxide. Ajayi AAL, n.u.l.l., Hercule, H.C., Pamugo, J., Dixon, D., Oyekan, A.O. Blood Press. (2001) [Pubmed]
  12. Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. Dib-Hajj, S.D., Tyrrell, L., Escayg, A., Wood, P.M., Meisler, M.H., Waxman, S.G. Genomics (1999) [Pubmed]
  13. Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. Dib-Hajj, S.D., Tyrrell, L., Cummins, T.R., Black, J.A., Wood, P.M., Waxman, S.G. FEBS Lett. (1999) [Pubmed]
  14. Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Agarwal, N., Offermanns, S., Kuner, R. Genesis (2004) [Pubmed]
  15. Muscle-derived neurotrophin-3 reduces injury-induced proprioceptive degeneration in neonatal mice. Wright, D.E., Williams, J.M., McDonald, J.T., Carlsten, J.A., Taylor, M.D. J. Neurobiol. (2002) [Pubmed]
  16. Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. Bray, G.A. Int. J. Obes. Relat. Metab. Disord. (2000) [Pubmed]
  17. Alteration of neurotransmitter phenotype in noradrenergic neurons of transgenic mice. Cadd, G.G., Hoyle, G.W., Quaife, C.J., Marck, B., Matsumoto, A.M., Brinster, R.L., Palmiter, R.D. Mol. Endocrinol. (1992) [Pubmed]
  18. Sympathetic nervous system does not mediate the load-induced cortical new bone formation. de Souza, R.L., Pitsillides, A.A., Lanyon, L.E., Skerry, T.M., Chenu, C. J. Bone Miner. Res. (2005) [Pubmed]
  19. Effects of 2-deoxy-D-glucose on the cardiac sympathetic nerves and the adrenal medulla in the rat: further evidence for a dissociation of sympathetic nervous system and adrenal medullary responses. Rappaport, E.B., Young, J.B., Landsberg, L. Endocrinology (1982) [Pubmed]
  20. Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons. Choi, J.S., Hudmon, A., Waxman, S.G., Dib-Hajj, S.D. J. Neurophysiol. (2006) [Pubmed]
  21. Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat. Kerr, N.C., Holmes, F.E., Wynick, D. J. Biol. Chem. (2004) [Pubmed]
  22. Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse. Kozak, C.A., Sangameswaran, L. Mamm. Genome (1996) [Pubmed]
  23. Contactin regulates the current density and axonal expression of tetrodotoxin-resistant but not tetrodotoxin-sensitive sodium channels in DRG neurons. Rush, A.M., Craner, M.J., Kageyama, T., Dib-Hajj, S.D., Waxman, S.G., Ranscht, B. Eur. J. Neurosci. (2005) [Pubmed]
  24. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Akopian, A.N., Souslova, V., England, S., Okuse, K., Ogata, N., Ure, J., Smith, A., Kerr, B.J., McMahon, S.B., Boyce, S., Hill, R., Stanfa, L.C., Dickenson, A.H., Wood, J.N. Nat. Neurosci. (1999) [Pubmed]
  25. An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen-induced arthritis. Härle, P., Möbius, D., Carr, D.J., Schölmerich, J., Straub, R.H. Arthritis Rheum. (2005) [Pubmed]
  26. Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice. Wang, S., Davis, B.M., Zwick, M., Waxman, S.G., Albers, K.M. Neurobiol. Aging (2006) [Pubmed]
  27. Autonomic regulation of experimental autoimmune encephalomyelitis in IL-4 knockout mice. Pál, E., Yamamura, T., Tabira, T. J. Neuroimmunol. (1999) [Pubmed]
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