6nt3

Structural highlights

Disease

SCN9A_HUMAN Channelopathy-associated congenital insensitivity to pain;Dravet syndrome;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Generalized epilepsy with febrile seizures-plus;Hereditary sensory and autonomic neuropathy type 2;Paroxysmal extreme pain disorder;Erythromelalgia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

SCN9A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]} SCNA1_PERAM Mediates the voltage-dependent sodium ion permeability of excitable membranes.[RuleBase:RU361132]^[11]

References

1. ↑ Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T. Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A. FEBS Lett. 2004 Jun 4;567(2-3):339-43. PMID:15178348 doi:http://dx.doi.org/10.1016/j.febslet.2004.04.092
2. ↑ Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci. 2004 Sep 22;24(38):8232-6. PMID:15385606 doi:http://dx.doi.org/10.1523/JNEUROSCI.2695-04.2004
3. ↑ Choi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006 Nov 14;67(9):1563-7. doi: 10.1212/01.wnl.0000231514.33603.1e., Epub 2006 Sep 20. PMID:16988069 doi:http://dx.doi.org/10.1212/01.wnl.0000231514.33603.1e
4. ↑ Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006. PMID:17145499 doi:http://dx.doi.org/10.1016/j.neuron.2006.10.006
5. ↑ Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894-8. PMID:17167479 doi:http://dx.doi.org/nature05413
6. ↑ Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, Cao X, Yang Y, Waxman SG. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain. 2009 Jul;132(Pt 7):1711-22. doi: 10.1093/brain/awp078. Epub 2009 Apr 15. PMID:19369487 doi:http://dx.doi.org/10.1093/brain/awp078
7. ↑ Eberhardt M, Nakajima J, Klinger AB, Neacsu C, Huhne K, O'Reilly AO, Kist AM, Lampe AK, Fischer K, Gibson J, Nau C, Winterpacht A, Lampert A. Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. J Biol Chem. 2014 Jan 24;289(4):1971-80. doi: 10.1074/jbc.M113.502211. Epub 2013 , Dec 5. PMID:24311784 doi:http://dx.doi.org/10.1074/jbc.M113.502211
8. ↑ Tan ZY, Priest BT, Krajewski JL, Knopp KL, Nisenbaum ES, Cummins TR. Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker. FEBS Lett. 2014 Nov 3;588(21):3964-9. doi: 10.1016/j.febslet.2014.09.011. Epub, 2014 Sep 19. PMID:25240195 doi:http://dx.doi.org/10.1016/j.febslet.2014.09.011
9. ↑ Ahuja S, Mukund S, Deng L, Khakh K, Chang E, Ho H, Shriver S, Young C, Lin S, Johnson JP Jr, Wu P, Li J, Coons M, Tam C, Brillantes B, Sampang H, Mortara K, Bowman KK, Clark KR, Estevez A, Xie Z, Verschoof H, Grimwood M, Dehnhardt C, Andrez JC, Focken T, Sutherlin DP, Safina BS, Starovasnik MA, Ortwine DF, Franke Y, Cohen CJ, Hackos DH, Koth CM, Payandeh J. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464. PMID:26680203 doi:http://dx.doi.org/10.1126/science.aac5464
10. ↑ Klugbauer N, Lacinova L, Flockerzi V, Hofmann F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 1995 Mar 15;14(6):1084-90. PMID:7720699
11. ↑ Shen H, Zhou Q, Pan X, Li Z, Wu J, Yan N. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science. 2017 Mar 3;355(6328). pii: eaal4326. doi: 10.1126/science.aal4326. Epub , 2017 Feb 9. PMID:28183995 doi:http://dx.doi.org/10.1126/science.aal4326