SCN7A

Template:Short description Template:Cs1 config An Error has occurred retrieving Wikidata item for infobox Na_x is a protein that in humans is encoded by the SCN7A (Sodium channel protein type 7) gene. 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 (Na_v1.1–1.9).

Function

Scientists 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).

Sodium sensor

Mouse Scn7a can be activated by changes in the extracellular concentration of sodium [~150 mM]. In this role it seems to be completely insensitive to tetrodotoxin, unlike its nine conventional VGNCs cousins.

Compared to normal mice, Scn7a knockout mice:

• Do not prefer water containing less sodium during dehydration.
• Do not have blood pressure increases following salt intake. Na_x are found on mouse sympathetic neurons and might be essential for this response.
• Show less regrowth of peripheral nerves after damage. It's unclear whether this process has anything to do with the putative sodium-sensor role.
• 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.

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.

Putative ion channel

The 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.

Evolution

Na_x is only found in eutherian mammals. It arose by a duplication of the gene SCN9A and quickly deviated from the canonical Na_v1 functions by losing key conserved residues in domains III, IV, and the loop in between. As eutherians diverged, Na_x showed exceptionally high evolutionary rates across all lineages.

Na_x must not be confused with "Na_v2" of invertebrates. This other "Na_v2" is a true voltage-gated channel in these animals and carry the ancestral "D/E/E/A" ion recognition sequence.

See also

• Sodium channel

Further reading

• 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, et al. (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): 507–519. doi:10.1016/j.cmet.2013.02.018. PMID 23541371.
• Shimizu H, Watanabe E, Hiyama TY, Nagakura A, Fujikawa A, Okado H, et al. (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): 9276–9281. doi:10.1523/JNEUROSCI.2795-04.2004. PMC 6730094. PMID 15496663.
• Meyers KJ, Mosley TH, Fox E, Boerwinkle E, Arnett DK, Devereux RB, et al. (May 2007). "Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks". Hypertension. 49 (5). Dallas, Tex.: 992–999. doi:10.1161/HYPERTENSIONAHA.106.081265. PMID 17339538.
• Zhang KX, Zhu DL, He X, Zhang Y, Zhang H, Zhao R, et al. (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): 463–467. PMID 14669210.
• Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, et al. (November 2000). "Nomenclature of voltage-gated sodium channels". Neuron. 28 (2): 365–368. 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, et al. (January 1994). "Assignment of a human voltage-dependent sodium channel alpha-subunit gene (SCN6A) to 2q21-q23". Genomics. 19 (2): 395–397. 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): 249–253. 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): 335–339. 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): 4893–4897. Bibcode:1992PNAS...89.4893G. doi:10.1073/pnas.89.11.4893. PMC 49194. PMID 1317577.

External links

• 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.