Nav1.4

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SCN4A
Identifiers
AliasesSCN4A, CMS16, HOKPP2, HYKPP, HYPP, NAC1A, Na(V)1.4, Nav1.4, SkM1, sodium voltage-gated channel alpha subunit 4
External IDsOMIM: 603967 MGI: 98250 HomoloGene: 283 GeneCards: SCN4A
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000334

NM_133199

RefSeq (protein)

NP_000325

NP_573462
NP_001390570

Location (UCSC)Chr 17: 63.94 – 63.97 MbChr 11: 106.21 – 106.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.[5][6][7][8]

The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.

Function

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders.[8]

Clinical significance

Periodic paralysis

In hypokalemic periodic paralysis, arginine residues making up the voltage sensor of Nav1.4 are mutated. The voltage sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of the protein, and contains basic residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In patients with these mutations, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise muscle. As a result, the muscle cannot contract efficiently, causing paralysis. The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.[9][10]

In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have also been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.[11][12]

In patients with these the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarized, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell in order to repolarise it to the resting potential, and this further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.[10]

Myotonia

The same types of mutations cause myotonia and paralysis, however the difference between these phenotypes depends on the level of sodium current that persists. If the conductance fluctuates below the voltage threshold for Nav1.4, then the sodium channels will eventually be able to close, and be depolarised again. Thus, the muscle merely remains contracted for longer than normal (myotonia) but will relax and be able to contract again within a short period. If the conductance settles at a steady state with the sodium pore open and unable to inactivate, then the muscle is unable to relax at all and motor control is completely lost (paralysis).

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000007314 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001027 - 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. ^ Ptacek LJ, Trimmer JS, Agnew WS, Roberts JW, Petajan JH, Leppert M (Oct 1991). "Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus". Am J Hum Genet. 49 (4): 851–4. PMC 1683172. PMID 1654742.
  6. ^ Ptacek LJ, George AL Jr, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF (Jan 1992). "Identification of a mutation in the gene causing hyperkalemic periodic paralysis". Cell. 67 (5): 1021–7. doi:10.1016/0092-8674(91)90374-8. PMID 1659948. S2CID 12539865.
  7. ^ Catterall WA, Goldin AL, Waxman SG (Dec 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacol Rev. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID 16382098. S2CID 7332624.
  8. ^ a b "Entrez Gene: SCN4A sodium channel, voltage-gated, type IV, alpha subunit".
  9. ^ Rüdel R, Lehmann-Horn F, Ricker K, Küther G (February 1984). "Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters". Muscle & Nerve. 7 (2): 110–20. doi:10.1002/mus.880070205. PMID 6325904. S2CID 25705002.
  10. ^ a b Jurkat-Rott K, Lehmann-Horn F (August 2005). "Muscle channelopathies and critical points in functional and genetic studies". The Journal of Clinical Investigation. 115 (8): 2000–9. doi:10.1172/JCI25525. PMC 1180551. PMID 16075040.
  11. ^ Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH (December 1991). "A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis". Nature. 354 (6352): 387–9. Bibcode:1991Natur.354..387R. doi:10.1038/354387a0. PMID 1659668. S2CID 4372717.
  12. ^ Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ (April 2002). "Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5". Neurology. 58 (8): 1266–72. doi:10.1212/wnl.58.8.1266. PMID 11971097. S2CID 10412539.

Further reading

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