Nav1.4 Explained

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.^{[1] [2] [3] [4]}

The Na_v1.4 voltage-gated sodium channel is encoded by the 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.^[4]

Clinical significance

Periodic paralysis

In hypokalemic periodic paralysis, arginine residues making up the voltage sensor of Na_v1.4 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.^{[5] [6]}

In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Na_v1.4. 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.^{[7] [8]}

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.^[6]

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 Na_v1.4, 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).

Further reading

• Ackerman MJ, Clapham DE . Ion channels--basic science and clinical disease . N. Engl. J. Med. . 336 . 22 . 1575–86 . 1997 . 9164815 . 10.1056/NEJM199705293362207 .
• Wang JZ . 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 . 1992 . 1310396 . 10.1016/0006-291X(92)91802-W . vanc. Rojas CV . Zhou JH . 3 . Schwartz . Lisa S. . Nicholas . Hugh . Hoffman . Eric P. .
• Ptacek LJ . Linkage of atypical myotonia congenita to a sodium channel locus . Neurology . 42 . 2 . 431–3 . 1992 . 1310531 . 10.1212/wnl.42.2.431. vanc. Tawil R . Griggs RC . 3 . Storvick . D . Leppert . M . 12480 .
• McClatchey AI . Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita . Cell . 68 . 4 . 769–74 . 1992 . 1310898 . 10.1016/0092-8674(92)90151-2 . vanc. Van den Bergh P . Pericak-Vance MA . 3 . Raskind . Wendy . Verellen . Christine . McKenna-Yasek . Diane . Rao . Keshav . Haines . Jonathan L. . Bird . Thomas . 31831830 .
• George AL, Komisarof J, Kallen RG, Barchi RL . Primary structure of the adult human skeletal muscle voltage-dependent sodium channel . Ann. Neurol. . 31 . 2 . 131–7 . 1992 . 1315496 . 10.1002/ana.410310203 . 37892568 .
• Ptácek LJ . Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita . Neuron . 8 . 5 . 891–7 . 1992 . 1316765 . 10.1016/0896-6273(92)90203-P . vanc. George AL . Barchi RL . 3 . Griggs . Robert C. . Riggs . Jack E. . Robertson . Margaret . Leppert . Mark F. . 41160865 .
• McClatchey AI . Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel . Nat. Genet. . 2 . 2 . 148–52 . 1993 . 1338909 . 10.1038/ng1092-148 . vanc. McKenna-Yasek D . Cros D . 3 . Worthen . Hilary G. . Kuncl . Ralph W. . Desilva . Shari M. . Cornblath . David R. . Gusella . James F. . Brown . Robert H. . 12492661 .
• McClatchey AI . The genomic structure of the human skeletal muscle sodium channel gene . Hum. Mol. Genet. . 1 . 7 . 521–7 . 1993 . 1339144 . 10.1093/hmg/1.7.521 . vanc. Lin CS . Wang J . 3 . p.Hoffman . Eric . Rojas . Cecilia . f.Gusella . James .
• Rojas CV . A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis . Nature . 354 . 6352 . 387–9 . 1992 . 1659668 . 10.1038/354387a0 . vanc. Wang JZ . Schwartz LS . 3 . Hoffman . Eric P. . Powell . Berkley R. . Brown Jr . Robert H. . 1991Natur.354..387R . 4372717 .
• George AL, Ledbetter DH, Kallen RG, Barchi RL . Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3 . Genomics . 9 . 3 . 555–6 . 1991 . 1851726 . 10.1016/0888-7543(91)90425-E . free .
• Fontaine B . Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene . Science . 250 . 4983 . 1000–2 . 1990 . 2173143 . 10.1126/science.2173143 . vanc. Khurana TS . Hoffman EP . 3 . Bruns . G. . Haines . J. . Trofatter . J. . Hanson . M. . Rich . J . McFarlane . H . 1990Sci...250.1000F .
• Plassart E . 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 . 1994 . 8044656 . 10.1159/000472351. vanc. Reboul J . Rime CS . 3 . Recan . D . Millasseau . P . Eymard . B . Pelletier . J . Thomas . C . Chapon . F . 7672692 .
• Ptáĉek LJ . Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis . Neurology . 44 . 8 . 1500–3 . 1994 . 8058156 . 10.1212/wnl.44.8.1500. vanc. Tawil R . Griggs RC . 3 . Meola . G . McManis . P . Barohn . RJ . Mendell . JR . Harris . C . Spitzer . R . 28470701 .
• Heine R, Pika U, Lehmann-Horn F . A novel SCN4A mutation causing myotonia aggravated by cold and potassium . Hum. Mol. Genet. . 2 . 9 . 1349–53 . 1993 . 8242056 . 10.1093/hmg/2.9.1349 .
• Lerche H . Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker . J. Physiol. . 470 . 13–22 . 1994 . 8308722 . 10.1113/jphysiol.1993.sp019843. 1143902 . vanc. Heine R . Pika U . 3 . George Jr . AL . Mitrovic . N . Browatzki . M . Weiss . T . Rivet-Bastide . M . Franke . C .
• George AL . Genomic organization of the human skeletal muscle sodium channel gene . Genomics . 15 . 3 . 598–606 . 1993 . 8385647 . 10.1006/geno.1993.1113 . vanc. Iyer GS . Kleinfield R . 3 . Kallen . Roland G. . Barchi . Robert L. . free .
• Ptacek LJ . Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis . Ann. Neurol. . 33 . 3 . 300–7 . 1993 . 8388676 . 10.1002/ana.410330312 . vanc. Gouw L . Kwieciński H . 3 . McManis . Philip . Mendell . Jerry R. . Barohn . Richard J. . George . Aflfred L. . Barchi . Rebert L. . Robertson . Margaret . 33366273 .

Notes and References

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