View source for Nav1.4

{{DISPLAYTITLE:Na<sub>v</sub>1.4}}
{{Infobox_gene}}
'''Sodium channel protein type 4 subunit alpha''' is a [[protein]] that in humans is encoded by the ''SCN4A'' [[gene]].<ref name="pmid1654742">{{cite journal |vauthors=Ptacek LJ, Trimmer JS, Agnew WS, Roberts JW, Petajan JH, Leppert M | title = Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus | journal = Am J Hum Genet | volume = 49 | issue = 4 | pages = 851–4 |date=Oct 1991 | pmid = 1654742 | pmc = 1683172 | doi =  }}</ref><ref name="pmid1659948">{{cite journal |vauthors=Ptacek LJ, ((George AL Jr)), Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF | title = Identification of a mutation in the gene causing hyperkalemic periodic paralysis | journal = Cell | volume = 67 | issue = 5 | pages = 1021–7 |date=Jan 1992 | pmid = 1659948 | pmc =  | doi =10.1016/0092-8674(91)90374-8  }}</ref><ref name="pmid16382098">{{cite journal |vauthors=Catterall WA, Goldin AL, Waxman SG | title = International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels | journal = Pharmacol Rev | volume = 57 | issue = 4 | pages = 397–409 |date=Dec 2005 | pmid = 16382098 | pmc =  | doi = 10.1124/pr.57.4.4 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SCN4A sodium channel, voltage-gated, type IV, alpha subunit| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6329| accessdate = }}</ref>

The '''Na<sub>v</sub>1.4'''  [[voltage-gated sodium channel]] is encoded by the {{Gene|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.<ref name="entrez"/>

==Clinical significance==

===Periodic paralysis===
In hypokalemic [[periodic paralysis]], [[arginine]] residues making up the [[voltage sensor]] of Na<sub>v</sub>1.4 are mutated. The voltage sensor comprises the S4 [[alpha helix]] of each of the four transmembrane domains (I-IV) of the protein, and contains [[Base (chemistry)|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.<ref name="pmid6325904">{{cite journal |vauthors=Rüdel R, Lehmann-Horn F, Ricker K, Küther G | title = Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters | journal = Muscle & Nerve | volume = 7 | issue = 2 | pages = 110–20 |date=February 1984 | pmid = 6325904 | doi = 10.1002/mus.880070205 | url =  }}</ref><ref name="Jurkat-Rott">{{cite journal |vauthors=Jurkat-Rott K, Lehmann-Horn F | title = Muscle channelopathies and critical points in functional and genetic studies | journal = The Journal of Clinical Investigation | volume = 115 | issue = 8 | pages = 2000–9 |date=August 2005 | pmid = 16075040 | pmc = 1180551 | doi = 10.1172/JCI25525 | url =  }}</ref>

In hyperkalemic periodic paralysis, mutations occur in residues between transmembrane domains III and IV which make up the fast inactivation gate of Na<sub>v</sub>1.4. 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.<ref name="pmid1659668">{{cite journal |vauthors=Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH | title = A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis | journal = Nature | volume = 354 | issue = 6352 | pages = 387–9 |date=December 1991 | pmid = 1659668 | doi = 10.1038/354387a0 | url =  }}</ref><ref name="pmid11971097">{{cite journal |vauthors=Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ | title = Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5 | journal = Neurology | volume = 58 | issue = 8 | pages = 1266–72 |date=April 2002 | pmid = 11971097 | doi = 10.1212/wnl.58.8.1266| url = http://www.neurology.org/cgi/content/abstract/58/8/1266 }}</ref>

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.<ref name="Jurkat-Rott"/>

===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<sub>v</sub>1.4, 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==
{{reflist}}

==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading 
| citations = 
*{{cite journal  |vauthors=Ackerman MJ, Clapham DE |title=Ion channels--basic science and clinical disease |journal=N. Engl. J. Med. |volume=336 |issue= 22 |pages= 1575–86 |year= 1997 |pmid= 9164815 |doi=10.1056/NEJM199705293362207  }}
*{{cite journal  | author=Wang JZ |title=Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 2 |pages= 794–801 |year= 1992 |pmid= 1310396 |doi=10.1016/0006-291X(92)91802-W  |name-list-format=vanc| author2=Rojas CV  | author3=Zhou JH  | display-authors=3  | last4=Schwartz  | first4=Lisa S.  | last5=Nicholas  | first5=Hugh  | last6=Hoffman  | first6=Eric P.  }}
*{{cite journal  | author=Ptacek LJ |title=Linkage of atypical myotonia congenita to a sodium channel locus |journal=Neurology |volume=42 |issue= 2 |pages= 431–3 |year= 1992 |pmid= 1310531 |doi=  10.1212/wnl.42.2.431|name-list-format=vanc| author2=Tawil R  | author3=Griggs RC  | display-authors=3  | last4=Storvick  | first4=D  | last5=Leppert  | first5=M  }}
*{{cite journal  | author=McClatchey AI |title=Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita |journal=Cell |volume=68 |issue= 4 |pages= 769–74 |year= 1992 |pmid= 1310898 |doi=10.1016/0092-8674(92)90151-2  |name-list-format=vanc| author2=Van den Bergh P  | author3=Pericak-Vance MA  | display-authors=3  | last4=Raskind  | first4=Wendy  | last5=Verellen  | first5=Christine  | last6=McKenna-Yasek  | first6=Diane  | last7=Rao  | first7=Keshav  | last8=Haines  | first8=Jonathan L.  | last9=Bird  | first9=Thomas  }}
*{{cite journal  |vauthors=George AL, Komisarof J, Kallen RG, Barchi RL |title=Primary structure of the adult human skeletal muscle voltage-dependent sodium channel |journal=Ann. Neurol. |volume=31 |issue= 2 |pages= 131–7 |year= 1992 |pmid= 1315496 |doi= 10.1002/ana.410310203 }}
*{{cite journal  | author=Ptácek LJ |title=Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita |journal=Neuron |volume=8 |issue= 5 |pages= 891–7 |year= 1992 |pmid= 1316765 |doi=10.1016/0896-6273(92)90203-P  |name-list-format=vanc| author2=George AL  | author3=Barchi RL  | display-authors=3  | last4=Griggs  | first4=Robert C.  | last5=Riggs  | first5=Jack E.  | last6=Robertson  | first6=Margaret  | last7=Leppert  | first7=Mark F.  }}
*{{cite journal  | author=McClatchey AI |title=Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel |journal=Nat. Genet. |volume=2 |issue= 2 |pages= 148–52 |year= 1993 |pmid= 1338909 |doi= 10.1038/ng1092-148  |name-list-format=vanc| author2=McKenna-Yasek D  | author3=Cros D  | display-authors=3  | last4=Worthen  | first4=Hilary G.  | last5=Kuncl  | first5=Ralph W.  | last6=Desilva  | first6=Shari M.  | last7=Cornblath  | first7=David R.  | last8=Gusella  | first8=James F.  | last9=Brown  | first9=Robert H. }}
*{{cite journal  | author=McClatchey AI |title=The genomic structure of the human skeletal muscle sodium channel gene |journal=Hum. Mol. Genet. |volume=1 |issue= 7 |pages= 521–7 |year= 1993 |pmid= 1339144 |doi=10.1093/hmg/1.7.521  |name-list-format=vanc| author2=Lin CS  | author3=Wang J  | display-authors=3  | last4=p.Hoffman  | first4=Eric  | last5=Rojas  | first5=Cecilia  | last6=f.Gusella  | first6=James  }}
*{{cite journal  | author=Rojas CV |title=A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis |journal=Nature |volume=354 |issue= 6352 |pages= 387–9 |year= 1992 |pmid= 1659668 |doi= 10.1038/354387a0  |name-list-format=vanc| author2=Wang JZ  | author3=Schwartz LS  | display-authors=3  | last4=Hoffman  | first4=Eric P.  | last5=Powell  | first5=Berkley R.  | last6=Brown Jr  | first6=Robert H. }}
*{{cite journal  |vauthors=George AL, Ledbetter DH, Kallen RG, Barchi RL |title=Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3 |journal=Genomics |volume=9 |issue= 3 |pages= 555–6 |year= 1991 |pmid= 1851726 |doi=10.1016/0888-7543(91)90425-E  }}
*{{cite journal  | author=Fontaine B |title=Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene |journal=Science |volume=250 |issue= 4983 |pages= 1000–2 |year= 1990 |pmid= 2173143 |doi=10.1126/science.2173143  |name-list-format=vanc| author2=Khurana TS  | author3=Hoffman EP  | display-authors=3  | last4=Bruns  | first4=G.  | last5=Haines  | first5=J.  | last6=Trofatter  | first6=J.  | last7=Hanson  | first7=M.  | last8=Rich  | first8=J  | last9=McFarlane  | first9=H  }}
*{{cite journal  | author=Plassart E |title=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 |journal=Eur. J. Hum. Genet. |volume=2 |issue= 2 |pages= 110–24 |year= 1994 |pmid= 8044656 |doi=  |name-list-format=vanc| author2=Reboul J  | author3=Rime CS  | display-authors=3  | last4=Recan  | first4=D  | last5=Millasseau  | first5=P  | last6=Eymard  | first6=B  | last7=Pelletier  | first7=J  | last8=Thomas  | first8=C  | last9=Chapon  | first9=F  }}
*{{cite journal  | author=Ptáĉek LJ |title=Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis |journal=Neurology |volume=44 |issue= 8 |pages= 1500–3 |year= 1994 |pmid= 8058156 |doi=  10.1212/wnl.44.8.1500|name-list-format=vanc| author2=Tawil R  | author3=Griggs RC  | display-authors=3  | last4=Meola  | first4=G  | last5=McManis  | first5=P  | last6=Barohn  | first6=RJ  | last7=Mendell  | first7=JR  | last8=Harris  | first8=C  | last9=Spitzer  | first9=R  }}
*{{cite journal  |vauthors=Heine R, Pika U, Lehmann-Horn F |title=A novel SCN4A mutation causing myotonia aggravated by cold and potassium |journal=Hum. Mol. Genet. |volume=2 |issue= 9 |pages= 1349–53 |year= 1993 |pmid= 8242056 |doi=10.1093/hmg/2.9.1349  }}
*{{cite journal  | author=Lerche H |title=Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker |journal=J. Physiol. |volume=470 |issue=  |pages= 13–22 |year= 1994 |pmid= 8308722 |doi=  10.1113/jphysiol.1993.sp019843| pmc=1143902  |name-list-format=vanc| author2=Heine R  | author3=Pika U  | display-authors=3  | last4=George Jr  | first4=AL  | last5=Mitrovic  | first5=N  | last6=Browatzki  | first6=M  | last7=Weiss  | first7=T  | last8=Rivet-Bastide  | first8=M  | last9=Franke  | first9=C  }}
*{{cite journal  | author=George AL |title=Genomic organization of the human skeletal muscle sodium channel gene |journal=Genomics |volume=15 |issue= 3 |pages= 598–606 |year= 1993 |pmid= 8385647 |doi= 10.1006/geno.1993.1113  |name-list-format=vanc| author2=Iyer GS  | author3=Kleinfield R  | display-authors=3  | last4=Kallen  | first4=Roland G.  | last5=Barchi  | first5=Robert L. }}
*{{cite journal  | author=Ptacek LJ |title=Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis |journal=Ann. Neurol. |volume=33 |issue= 3 |pages= 300–7 |year= 1993 |pmid= 8388676 |doi= 10.1002/ana.410330312  |name-list-format=vanc| author2=Gouw L  | author3=Kwieciński H  | display-authors=3  | last4=McManis  | first4=Philip  | last5=Mendell  | first5=Jerry R.  | last6=Barohn  | first6=Richard J.  | last7=George  | first7=Aflfred L.  | last8=Barchi  | first8=Rebert L.  | last9=Robertson  | first9=Margaret }}
}}
{{refend}}

{{PDB Gallery|geneid=6329}}
{{Ion channels|g2}}

{{NLM content}}

<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{PBB_Controls
| update_page = yes 
| require_manual_inspection = no 
| update_protein_box = yes
| update_summary = no
| update_citations = yes
}}

[[Category:Electrophysiology]]
[[Category:Sodium channels]]