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The crystal 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, along with the known phenomenon of [[hydrophobic gating]], suggests that SCN7A could actually function as an ion channel, assuming there is a way to displace the lipid molecules ''in vivo''.<ref name="wetpore"/>
The crystal 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, along with the known phenomenon of [[hydrophobic gating]], suggests that SCN7A could actually function as an ion channel, assuming there is a way to displace the lipid molecules ''in vivo''.<ref name="wetpore"/>

== Evolution ==
Na<sub>x</sub> is only found in [[eutherian]] mammals. It arose by a duplication of the gene [[SCN9A]] and quickly deviated from the canonical Na<sub>v</sub>1 functions by losing key conserved residues in domains III, IV, and the loop in between. As eutherians diverged, Na<sub>x</sub> showed exceptionally high evolutionary rates across all lineages.<ref>{{cite journal |last1=Widmark |first1=J |last2=Sundström |first2=G |last3=Ocampo Daza |first3=D |last4=Larhammar |first4=D |title=Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes. |journal=Molecular biology and evolution |date=January 2011 |volume=28 |issue=1 |pages=859-71 |doi=10.1093/molbev/msq257 |pmid=20924084 |doi-access=free}}</ref>

Na<sub>x</sub> must not be confused with "Na<sub>v</sub>2" of invertebrates. This other "Na<sub>v</sub>2" is a true voltage-gated channel in these animals and carry the ancestral "D/E/E/A" sequence.<ref>{{cite journal |last1=Liebeskind |first1=BJ |last2=Hillis |first2=DM |last3=Zakon |first3=HH |title=Evolution of sodium channels predates the origin of nervous systems in animals. |journal=Proceedings of the National Academy of Sciences of the United States of America |date=31 May 2011 |volume=108 |issue=22 |pages=9154-9 |doi=10.1073/pnas.1106363108 |pmid=21576472}}</ref>


== See also ==
== See also ==

Revision as of 10:44, 26 November 2023

SCN7A
Identifiers
AliasesSCN7A, NaG, Nav2.1, Nav2.2, SCN6A, sodium voltage-gated channel alpha subunit 7
External IDsOMIM: 182392; MGI: 102965; HomoloGene: 55706; GeneCards: SCN7A; OMA:SCN7A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6332

20272

Ensembl

ENSG00000136546

ENSMUSG00000034810

UniProt

Q01118

n/a

RefSeq (mRNA)

NM_002976

NM_009135

RefSeq (protein)

NP_002967

n/a

Location (UCSC)Chr 2: 166.4 – 166.61 MbChr 2: 66.5 – 66.62 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sodium channel protein type 7 subunit alpha is a protein that in humans is encoded by the SCN7A gene on the chromosome specifically located at 2q21-23 chromosome site.[5][6] It encodes the sodium channel alpha subunit Nax, also called Nav2, Nav2.1, Nav2.3, or NaG.[7]

Nax is 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]

Function

Scientists have so far been unable to create a voltage-gated channel out of SCN7A. There are so far two theories to its purpose: sodium sensor (confirmed in rats, not reproducible in human cells), and ion channel (proposed for humans).[8]

Sodium sensor

Mouse Scn7a can be activated by changes in the extracellular concentration of sodium [~150 mM].[7] 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 proces has anything to do with the putated 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.[8]

Putative ion channel

The crystal 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, along with the known phenomenon of hydrophobic gating, suggests that SCN7A could actually function as an ion channel, assuming there is a way to displace the lipid molecules in vivo.[8]

Evolution

Nax 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" sequence.[15]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136546 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034810 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ "Entrez Gene: SCN7A sodium channel, voltage-gated, type VII, alpha".
  7. ^ a b 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.
  8. ^ 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). doi:10.1038/s41467-022-28984-4.
  9. ^ 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.
  10. ^ 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 : the official journal of the Society for Neuroscience. 20 (20): 7743–51. doi:10.1523/JNEUROSCI.20-20-07743.2000. PMID 11027237.
  11. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ 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. PMID 24730033.
  13. ^ 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 : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 29 (2): 306–315. doi:10.1111/wrr.12885. PMID 33378794.
  14. ^ 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.
  15. ^ 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. doi:10.1073/pnas.1106363108. PMID 21576472.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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