Biology:Nav1.4

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

The Na_v1.4 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.

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.

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.

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.

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

• "Ion channels--basic science and clinical disease". N. Engl. J. Med. 336 (22): 1575–86. 1997. doi:10.1056/NEJM199705293362207. PMID 9164815. 
• 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. PMID 1310396. 
• Ptacek LJ; Tawil R; Griggs RC et al. (1992). "Linkage of atypical myotonia congenita to a sodium channel locus". Neurology 42 (2): 431–3. doi:10.1212/wnl.42.2.431. PMID 1310531. 
• McClatchey AI; Van den Bergh P; Pericak-Vance MA et al. (1992). "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. doi:10.1016/0092-8674(92)90151-2. PMID 1310898. 
• "Primary structure of the adult human skeletal muscle voltage-dependent sodium channel". Ann. Neurol. 31 (2): 131–7. 1992. doi:10.1002/ana.410310203. PMID 1315496. 
• 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. PMID 1316765. 
• 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. PMID 1338909. 
• McClatchey AI; Lin CS; Wang J et al. (1993). "The genomic structure of the human skeletal muscle sodium channel gene". Hum. Mol. Genet. 1 (7): 521–7. doi:10.1093/hmg/1.7.521. PMID 1339144. 
• Rojas CV; Wang JZ; Schwartz LS et al. (1992). "A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis". Nature 354 (6352): 387–9. doi:10.1038/354387a0. PMID 1659668. Bibcode: 1991Natur.354..387R. 
• "Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3". Genomics 9 (3): 555–6. 1991. doi:10.1016/0888-7543(91)90425-E. PMID 1851726. 
• Fontaine B; Khurana TS; Hoffman EP et al. (1990). "Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene". Science 250 (4983): 1000–2. doi:10.1126/science.2173143. PMID 2173143. Bibcode: 1990Sci...250.1000F. 
• 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. PMID 8044656. 
• Ptáĉek LJ; Tawil R; Griggs RC et al. (1994). "Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis". Neurology 44 (8): 1500–3. doi:10.1212/wnl.44.8.1500. PMID 8058156. 
• "A novel SCN4A mutation causing myotonia aggravated by cold and potassium". Hum. Mol. Genet. 2 (9): 1349–53. 1993. doi:10.1093/hmg/2.9.1349. PMID 8242056. 
• Lerche H; Heine R; Pika U et al. (1994). "Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker". J. Physiol. 470: 13–22. doi:10.1113/jphysiol.1993.sp019843. PMID 8308722. 
• George AL; Iyer GS; Kleinfield R et al. (1993). "Genomic organization of the human skeletal muscle sodium channel gene". Genomics 15 (3): 598–606. doi:10.1006/geno.1993.1113. PMID 8385647. 
• Ptacek LJ; Gouw L; Kwieciński H et al. (1993). "Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis". Ann. Neurol. 33 (3): 300–7. doi:10.1002/ana.410330312. PMID 8388676. 

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