SCN7A explained

Na_x is a protein that in humans is encoded by the SCN7A (Sodium channel protein type 7) gene.^{[1] [2]} 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).^[1]

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].^[3] In this role it seems to be completely insensitve to tetrodotoxin, unlike its nine conventional VGNCs cousins.^[4]

Compared to normal mice, Scn7a knockout mice:

• Do not prefer water containing less sodium during dehydration.^[5]
• Do not have blood pressure increases following salt intake. Na_x are found on mouse sympathetic neurons and might be essential for this response.^[6]
• Show less regrowth of peripheral nerves after damage. It's unclear whether this process has anything to do with the putative sodium-sensor role.^[7]
• 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.^[8]

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.^[9]

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.^[9]

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.^[10]

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.^[11]

See also

• Sodium channel

Further reading

• Noda M, Hiyama TY . The Na(x) Channel: What It Is and What It Does . The Neuroscientist . 21 . 4 . 399–412 . August 2015 . 24962095 . 10.1177/1073858414541009 . 10726163 .
• Hiyama TY, Yoshida M, Matsumoto M, Suzuki R, Matsuda T, Watanabe E, Noda M . 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 . April 2013 . 23541371 . 10.1016/j.cmet.2013.02.018 . free .
• Shimizu H, Watanabe E, Hiyama TY, Nagakura A, Fujikawa A, Okado H, Yanagawa Y, Obata K, Noda M . Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing . Neuron . 54 . 1 . 59–72 . April 2007 . 17408578 . 10.1016/j.neuron.2007.03.014 . 16616098 . free .
• Hiyama TY, Watanabe E, Okado H, Noda M . 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 . October 2004 . 15496663 . 6730094 . 10.1523/JNEUROSCI.2795-04.2004 .
• Meyers KJ, Mosley TH, Fox E, Boerwinkle E, Arnett DK, Devereux RB, Kardia SL . Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks . Hypertension . 49 . 5 . 992–9 . May 2007 . 17339538 . 10.1161/HYPERTENSIONAHA.106.081265 . free .
• Zhang KX, Zhu DL, He X, Zhang Y, Zhang H, Zhao R, Lin J, Wang GL, Zhang KY, Huang W . [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 . December 2003 . 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 . Nomenclature of voltage-gated sodium channels . Neuron . 28 . 2 . 365–8 . November 2000 . 11144347 . 10.1016/S0896-6273(00)00116-1 . 14687170 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• George AL, Knops JF, Han J, Finley WH, Knittle TJ, Tamkun MM, Brown GB . Assignment of a human voltage-dependent sodium channel alpha-subunit gene (SCN6A) to 2q21-q23 . Genomics . 19 . 2 . 395–7 . January 1994 . 8188276 . 10.1006/geno.1994.1081 .
• Boyle MB, Heslip LA . Voltage-dependent Na+ channel mRNA expression in pregnant myometrium . Receptors & Channels . 2 . 3 . 249–53 . 1995 . 7874451 .
• Han JA, Lu CM, Brown GB, Rado TA . 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 . January 1991 . 1846440 . 50805 . 10.1073/pnas.88.2.335 . 1991PNAS...88..335H . free .
• George AL, Knittle TJ, Tamkun MM . 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 . June 1992 . 1317577 . 49194 . 10.1073/pnas.89.11.4893 . 1992PNAS...89.4893G . free .

Notes and References

1. Plummer NW, Meisler MH . Evolution and diversity of mammalian sodium channel genes . Genomics . 57 . 2 . 323–31 . April 1999 . 10198179 . 10.1006/geno.1998.5735 .
2. Web site: Entrez Gene: SCN7A sodium channel, voltage-gated, type VII, alpha.
3. Hiyama TY, Watanabe E, Ono K, Inenaga K, Tamkun MM, Yoshida S, Noda M . Na(x) channel involved in CNS sodium-level sensing . Nature Neuroscience . 5 . 6 . 511–2 . June 2002 . 11992118 . 10.1038/nn0602-856 . 2994021 .
4. Grob . Magali . Drolet . Guy . Mouginot . Didier . Specific Na + Sensors Are Functionally Expressed in a Neuronal Population of the Median Preoptic Nucleus of the Rat . The Journal of Neuroscience . 21 April 2004 . 24 . 16 . 3974–3984 . 10.1523/JNEUROSCI.3720-03.2004. 15102913 . 6729411 .
5. Watanabe . E . Fujikawa . A . Matsunaga . H . Yasoshima . Y . Sako . N . Yamamoto . T . Saegusa . C . Noda . M . Nav2/NaG channel is involved in control of salt-intake behavior in the CNS. . The Journal of Neuroscience . 15 October 2000 . 20 . 20 . 7743–51 . 10.1523/JNEUROSCI.20-20-07743.2000 . 11027237. 6772860 .
6. Davis . Harvey . Paterson . David J . Herring . Neil . Post-Ganglionic Sympathetic Neurons can Directly Sense Raised Extracellular Na+ via SCN7a/Nax . Frontiers in Physiology . 17 June 2022 . 13 . 10.3389/fphys.2022.931094 . 35784866 . 9247455 . free .
7. Unezaki . Sawako . Katano . Tayo . Hiyama . Takeshi Y. . Tu . Nguyen H. . Yoshii . Satoru . Noda . Masaharu . Ito . Seiji . Involvement of Nax sodium channel in peripheral nerve regeneration via lactate signaling . The European Journal of Neuroscience . March 2014 . 39 . 5 . 720–729 . 10.1111/ejn.12436 . 24730033. 40587577 .
8. Hou . C . Dolivo . D . Rodrigues . A . Li . Y . Leung . K . Galiano . R . Hong . SJ . Mustoe . T . Knockout of sodium channel Na(x) delays re-epithelializathion of splinted murine excisional wounds. . Wound Repair and Regeneration . March 2021 . 29 . 2 . 306–315 . 10.1111/wrr.12885 . 33378794. 229930076 .
9. 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 . Structure-guided unlocking of NaX reveals a non-selective tetrodotoxin-sensitive cation channel . Nature Communications . 17 March 2022 . 13 . 1 . 1416 . 10.1038/s41467-022-28984-4 . 35301303 . 8931054 . 2022NatCo..13.1416N . free.
10. Widmark . J . Sundström . G . Ocampo Daza . D . Larhammar . D . Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes. . Molecular Biology and Evolution . January 2011 . 28 . 1 . 859–71 . 10.1093/molbev/msq257 . 20924084 . free.
11. Liebeskind . BJ . Hillis . DM . Zakon . HH . 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 . 31 May 2011 . 108 . 22 . 9154–9 . 10.1073/pnas.1106363108 . 21576472 . 3107268 . 2011PNAS..108.9154L . free .