Voltage-gated sodium channels aretransmembraneglycoprotein complexes composed of a large alpha subunit with 24transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation ofaction potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed inskeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders.[8]
In hypokalemicperiodic paralysis,arginine residues making up thevoltage sensor of Nav1.4 are mutated. The voltage sensor comprises the S4alpha helix of each of the four transmembrane domains (I-IV) of the protein, and containsbasic 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 todepolarise 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 theresting 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 themotor 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 theresting 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]
The same types of mutations causemyotonia 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).
^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.PMID1659948.S2CID12539865.
^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.PMID16382098.S2CID7332624.
^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.PMID1659668.S2CID4372717.
Wang JZ, Rojas CV, Zhou JH, et al. (1992). "Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q".Biochem. Biophys. Res. Commun.182 (2):794–801.doi:10.1016/0006-291X(92)91802-W.PMID1310396.
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Ptácek LJ, George AL, Barchi RL, et al. (1992). "Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita".Neuron.8 (5):891–7.doi:10.1016/0896-6273(92)90203-P.PMID1316765.S2CID41160865.
McClatchey AI, McKenna-Yasek D, Cros D, et al. (1993). "Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel".Nat. Genet.2 (2):148–52.doi:10.1038/ng1092-148.PMID1338909.S2CID12492661.
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Plassart E, Reboul J, Rime CS, et al. (1994). "Mutations in the muscle sodium channel gene (SCN4A) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: phenotype to genotype correlations and demonstration of the predominance of two mutations".Eur. J. Hum. Genet.2 (2):110–24.doi:10.1159/000472351.PMID8044656.S2CID7672692.
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