Nax is a protein that in humans is encoded by the SCN7A (Sodium channel protein type 7) gene.[5][6] It is a sodium channel alpha subunit expressed in the heart, the uterus and in glial cells of mice. It has low similarity to all nine other sodium channel alpha subunits (Nav1.1–1.9).[5]
| SCN7A | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | SCN7A, NaG, Nav2.1, Nav2.2, SCN6A, sodium voltage-gated channel alpha subunit 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 182392; MGI: 102965; HomoloGene: 55706; GeneCards: SCN7A; OMA:SCN7A - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Function
editScientists have so far been unable to create a voltage-gated channel out of SCN7A. There are two theories to its purpose: sodium sensor (confirmed in rats, not reproducible in human cells), and ion channel (proposed for humans).[7]
Sodium sensor
editMouse Scn7a can be activated by changes in the extracellular concentration of sodium [~150 mM].[8] In this role it seems to be completely insensitve to tetrodotoxin, unlike its nine conventional VGNCs cousins.[9]
Compared to normal mice, Scn7a knockout mice:
- Do not prefer water containing less sodium during dehydration.[10]
- Do not have blood pressure increases following salt intake. Nax are found on mouse sympathetic neurons and might be essential for this response.[11]
- Show less regrowth of peripheral nerves after damage. It's unclear whether this process has anything to do with the putative sodium-sensor role.[12]
- Heal wounds slower. Scn7a has previously been shown to play a role in maintaining the sodium concentration in epithelial cells. Mice with a temporary knockdown via DSIRNA also show delayed healing.[13]
Despite all the evidence pointing to Scn7a acting as a sodium sensor in rodents, there is no data for humans, not even in cell cultures. Conditions that confirm the sodium-sensing abilities of mouse Scn7a do not reliably work on human SCN7A.[7]
Putative ion channel
editThe cyro-EM structure shows that human SCN7A is normally stuck in a nonconductive state, with several membrane lipid molecules blocking the pore. When three polar "QTT" mutations were added to drive the lipids away from SCN7A, one obtains a leakage channel that is always active. SCN7A-QTT does not discriminate among monovalent cations, is inhibited by extracellular calcium, and is sensitive to tetrodotoxin and other classical sodium channel blockers. This result suggests that SCN7A could actually function as an ion channel, assuming there is a way to displace the lipid molecules in vivo – this type of "hydrophobic gating" is not unheard of in other channels.[7]
Evolution
editNax is only found in eutherian mammals. It arose by a duplication of the gene SCN9A and quickly deviated from the canonical Nav1 functions by losing key conserved residues in domains III, IV, and the loop in between. As eutherians diverged, Nax showed exceptionally high evolutionary rates across all lineages.[14]
Nax must not be confused with "Nav2" of invertebrates. This other "Nav2" is a true voltage-gated channel in these animals and carry the ancestral "D/E/E/A" ion recognition sequence.[15]
See also
editReferences
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000136546 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034810 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b 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.
- ^ "Entrez Gene: SCN7A sodium channel, voltage-gated, type VII, alpha".
- ^ a b c Noland, Cameron L.; Chua, Han Chow; Kschonsak, Marc; Heusser, Stephanie Andrea; Braun, Nina; Chang, Timothy; Tam, Christine; Tang, Jia; Arthur, Christopher P.; Ciferri, Claudio; Pless, Stephan Alexander; Payandeh, Jian (17 March 2022). "Structure-guided unlocking of NaX reveals a non-selective tetrodotoxin-sensitive cation channel". Nature Communications. 13 (1): 1416. Bibcode:2022NatCo..13.1416N. doi:10.1038/s41467-022-28984-4. PMC 8931054. PMID 35301303.
- ^ Hiyama TY, Watanabe E, Ono K, Inenaga K, Tamkun MM, Yoshida S, Noda M (June 2002). "Na(x) channel involved in CNS sodium-level sensing". Nature Neuroscience. 5 (6): 511–2. doi:10.1038/nn0602-856. PMID 11992118. S2CID 2994021.
- ^ Grob, Magali; Drolet, Guy; Mouginot, Didier (21 April 2004). "Specific Na + Sensors Are Functionally Expressed in a Neuronal Population of the Median Preoptic Nucleus of the Rat". The Journal of Neuroscience. 24 (16): 3974–3984. doi:10.1523/JNEUROSCI.3720-03.2004. PMC 6729411. PMID 15102913.
- ^ Watanabe, E; Fujikawa, A; Matsunaga, H; Yasoshima, Y; Sako, N; Yamamoto, T; Saegusa, C; Noda, M (15 October 2000). "Nav2/NaG channel is involved in control of salt-intake behavior in the CNS". The Journal of Neuroscience. 20 (20): 7743–51. doi:10.1523/JNEUROSCI.20-20-07743.2000. PMC 6772860. PMID 11027237.
- ^ Davis, Harvey; Paterson, David J; Herring, Neil (17 June 2022). "Post-Ganglionic Sympathetic Neurons can Directly Sense Raised Extracellular Na+ via SCN7a/Nax". Frontiers in Physiology. 13. doi:10.3389/fphys.2022.931094. PMC 9247455. PMID 35784866.
- ^ Unezaki, Sawako; Katano, Tayo; Hiyama, Takeshi Y.; Tu, Nguyen H.; Yoshii, Satoru; Noda, Masaharu; Ito, Seiji (March 2014). "Involvement of Nax sodium channel in peripheral nerve regeneration via lactate signaling". The European Journal of Neuroscience. 39 (5): 720–729. doi:10.1111/ejn.12436. PMID 24730033. S2CID 40587577.
- ^ Hou, C; Dolivo, D; Rodrigues, A; Li, Y; Leung, K; Galiano, R; Hong, SJ; Mustoe, T (March 2021). "Knockout of sodium channel Na(x) delays re-epithelializathion of splinted murine excisional wounds". Wound Repair and Regeneration. 29 (2): 306–315. doi:10.1111/wrr.12885. PMID 33378794. S2CID 229930076.
- ^ Widmark, J; Sundström, G; Ocampo Daza, D; Larhammar, D (January 2011). "Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes". Molecular Biology and Evolution. 28 (1): 859–71. doi:10.1093/molbev/msq257. PMID 20924084.
- ^ Liebeskind, BJ; Hillis, DM; Zakon, HH (31 May 2011). "Evolution of sodium channels predates the origin of nervous systems in animals". Proceedings of the National Academy of Sciences of the United States of America. 108 (22): 9154–9. Bibcode:2011PNAS..108.9154L. doi:10.1073/pnas.1106363108. PMC 3107268. PMID 21576472.
Further reading
edit- Noda M, Hiyama TY (August 2015). "The Na(x) Channel: What It Is and What It Does". The Neuroscientist. 21 (4): 399–412. doi:10.1177/1073858414541009. PMID 24962095. S2CID 10726163.
- Hiyama TY, Yoshida M, Matsumoto M, Suzuki R, Matsuda T, Watanabe E, Noda M (April 2013). "Endothelin-3 expression in the subfornical organ enhances the sensitivity of Na(x), the brain sodium-level sensor, to suppress salt intake". Cell Metabolism. 17 (4): 507–19. doi:10.1016/j.cmet.2013.02.018. PMID 23541371.
- Shimizu H, Watanabe E, Hiyama TY, Nagakura A, Fujikawa A, Okado H, Yanagawa Y, Obata K, Noda M (April 2007). "Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing". Neuron. 54 (1): 59–72. doi:10.1016/j.neuron.2007.03.014. PMID 17408578. S2CID 16616098.
- Hiyama TY, Watanabe E, Okado H, Noda M (October 2004). "The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior". The Journal of Neuroscience. 24 (42): 9276–81. doi:10.1523/JNEUROSCI.2795-04.2004. PMC 6730094. PMID 15496663.
- Meyers KJ, Mosley TH, Fox E, Boerwinkle E, Arnett DK, Devereux RB, Kardia SL (May 2007). "Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks". Hypertension. 49 (5): 992–9. doi:10.1161/HYPERTENSIONAHA.106.081265. PMID 17339538.
- Zhang KX, Zhu DL, He X, Zhang Y, Zhang H, Zhao R, Lin J, Wang GL, Zhang KY, Huang W (December 2003). "[Association of single nucleotide polymorphism in human SCN7A gene with essential hypertension in Chinese]". Zhonghua Yi Xue Yi Chuan Xue Za Zhi = Zhonghua Yixue Yichuanxue Zazhi = Chinese Journal of Medical Genetics. 20 (6): 463–7. PMID 14669210.
- Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB, Noda M, Tamkun MM, Waxman SG, Wood JN, Catterall WA (November 2000). "Nomenclature of voltage-gated sodium channels". Neuron. 28 (2): 365–8. doi:10.1016/S0896-6273(00)00116-1. PMID 11144347. S2CID 14687170.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- George AL, Knops JF, Han J, Finley WH, Knittle TJ, Tamkun MM, Brown GB (January 1994). "Assignment of a human voltage-dependent sodium channel alpha-subunit gene (SCN6A) to 2q21-q23". Genomics. 19 (2): 395–7. doi:10.1006/geno.1994.1081. PMID 8188276.
- Boyle MB, Heslip LA (1995). "Voltage-dependent Na+ channel mRNA expression in pregnant myometrium". Receptors & Channels. 2 (3): 249–53. PMID 7874451.
- Han JA, Lu CM, Brown GB, Rado TA (January 1991). "Direct amplification of a single dissected chromosomal segment by polymerase chain reaction: a human brain sodium channel gene is on chromosome 2q22-q23". Proceedings of the National Academy of Sciences of the United States of America. 88 (2): 335–9. Bibcode:1991PNAS...88..335H. doi:10.1073/pnas.88.2.335. PMC 50805. PMID 1846440.
- George AL, Knittle TJ, Tamkun MM (June 1992). "Molecular cloning of an atypical voltage-gated sodium channel expressed in human heart and uterus: evidence for a distinct gene family". Proceedings of the National Academy of Sciences of the United States of America. 89 (11): 4893–7. Bibcode:1992PNAS...89.4893G. doi:10.1073/pnas.89.11.4893. PMC 49194. PMID 1317577.
External links
edit- SCN7A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Online Mendelian Inheritance in Man (OMIM): 182392
This article incorporates text from the United States National Library of Medicine, which is in the public domain.