SCN5A Membrane Protein Introduction

Introduction of SCN5A

The sodium channel protein type 5 subunit alpha (Nav1.5) is encoded by the SCN5A gene located on chromosome 3p21. SCN5A is highly conserved across species and contains four structurally homologous domains (DI-DIV), composed of six transmembrane helices (S1-S6) each, linked by intra- or extracellular loops. The cardiac Na⁺ channel forms a macromolecular, multiprotein complex consisting of SCN5A, auxiliary proteins like the beta subunits (SCN1B, SCN2B, SCN3B, and SCN4B) and regulatory proteins like telethonin (encoded by the TCAP gene).

Basic Information of SCN5A
Protein Name	Sodium channel protein type 5 subunit alpha
Gene Name	SCN5A
Aliases	Sodium channel protein cardiac muscle subunit alpha, Sodium channel protein type V subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.5
Organism	Homo sapiens (Human)
UniProt ID	Q14524
Transmembrane Times	24
Length (aa)	2016
Sequence	MANFLLPRGTSSFRRFTRESLAAIEKRMAEKQARGSTTLQESREGLPEEEAPRPQLDLQASKKLPDLYGNPPQELIGEPLEDLDPFYSTQKTFIVLNKGKTIFRFSATNALYVLSPFHPIRRAAVKILVHSLFNMLIMCTILTNCVFMAQHDPPPWTKYVEYTFTAIYTFESLVKILARGFCLHAFTFLRDPWNWLDFSVIIMAYTTEFVDLGNVSALRTFRVLRALKTISVISGLKTIVGALIQSVKKLADVMVLTVFCLSVFALIGLQLFMGNLRHKCVRNFTALNGTNGSVEADGLVWESLDLYLSDPENYLLKNGTSDVLLCGNSSDAGTCPEGYRCLKAGENPDHGYTSFDSFAWAFLALFRLMTQDCWERLYQQTLRSAGKIYMIFFMLVIFLGSFYLVNLILAVVAMAYEEQNQATIAETEEKEKRFQEAMEMLKKEHEALTIRGVDTVSRSSLEMSPLAPVNSHERRSKRRKRMSSGTEECGEDRLPKSDSEDGPRAMNHLSLTRGLSRTSMKPRSSRGSIFTFRRRDLGSEADFADDENSTAGESESHHTSLLVPWPLRRTSAQGQPSPGTSAPGHALHGKKNSTVDCNGVVSLLGAGDPEATSPGSHLLRPVMLEHPPDTTTPSEEPGGPQMLTSQAPCVDGFEEPGARQRALSAVSVLTSALEELEESRHKCPPCWNRLAQRYLIWECCPLWMSIKQGVKLVVMDPFTDLTITMCIVLNTLFMALEHYNMTSEFEEMLQVGNLVFTGIFTAEMTFKIIALDPYYYFQQGWNIFDSIIVILSLMELGLSRMSNLSVLRSFRLLRVFKLAKSWPTLNTLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQLFGKNYSELRDSDSGLLPRWHMMDFFHAFLIIFRILCGEWIETMWDCMEVSGQSLCLLVFLLVMVIGNLVVLNLFLALLLSSFSADNLTAPDEDREMNNLQLALARIQRGLRFVKRTTWDFCCGLLRQRPQKPAALAAQGQLPSCIATPYSPPPPETEKVPPTRKETRFEEGEQPGQGTPGDPEPVCVPIAVAESDTDDQEEDEENSLGTEEESSKQQESQPVSGGPEAPPDSRTWSQVSATASSEAEASASQADWRQQWKAEPQAPGCGETPEDSCSEGSTADMTNTAELLEQIPDLGQDVKDPEDCFTEGCVRRCPCCAVDTTQAPGKVWWRLRKTCYHIVEHSWFETFIIFMILLSSGALAFEDIYLEERKTIKVLLEYADKMFTYVFVLEMLLKWVAYGFKKYFTNAWCWLDFLIVDVSLVSLVANTLGFAEMGPIKSLRTLRALRPLRALSRFEGMRVVVNALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFGRCINQTEGDLPLNYTIVNNKSQCESLNLTGELYWTKVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRGYEEQPQWEYNLYMYIYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGQDIFMTEEQKKYYNAMKKLGSKKPQKPIPRPLNKYQGFIFDIVTKQAFDVTIMFLICLNMVTMMVETDDQSPEKINILAKINLLFVAIFTGECIVKLAALRHYYFTNSWNIFDFVVVILSIVGTVLSDIIQKYFFSPTLFRVIRLARIGRILRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFGMANFAYVKWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPPYCDPTLPNSNGSRGDCGSPAVGILFFTTYIIISFLIVVNMYIAIILENFSVATEESTEPLSEDDFDMFYEIWEKFDPEATQFIEYSVLSDFADALSEPLRIAKPNQISLINMDLPMVSGDRIHCMDILFAFTKRVLGESGEMDALKIQMEEKFMAANPSKISYEPITTTLRRKHEEVSAMVIQRAFRRHLLQRSLKHASFLFRQQAGSGLSEEDAPEREGLIAYVMSENFSRPLGPPSSSSISSTSFPPSYDSVTRATSDNLQVRGSDYSHSEDLADFPPSPDRDRESIV

Function of SCN5A Membrane Protein

The alpha subunit of the voltage-dependent sodium channel including SCN5A, enables the rapid influx of Na⁺ ions (INa). Voltage-gated Na⁺ channels are crucial in the excitation and propagation of electrical impulses in excitable cells, such as cardiomyocytes or nerves. SCN5A is expressed in human cardiomyocytes, embryonic and denervated skeletal muscle cells. SCN5A is responsible for the fast depolarization and generation of the cardiac action potential (AP) and conduction of the cardiac AP. SCN5A mutations are implied to disrupt cardiac electrical stability and described in several inherited arrhythmia syndromes, such as the long-QT syndrome type 3 (LQT3), Brugada syndrome progressive cardiac conduction disease, sinus node dysfunction, atrial fibrillation, dilated cardiomyopathy and multifocal ectopic Purkinje-related premature contractions.

Fig.1 Rare and disease-associated SCN5A variants in atrial fibrillation probands illustrated by position within the sodium channel protein topology. (Darbar, 2008)

Application of SCN5A Membrane Protein in Literature

Qureshi S.F., et al. Mutational analysis of SCN5A gene in long QT syndrome. Meta Gene. 2015, 6:26-35. PubMed ID: 26401487

This article finds that compound heterozygotes of SCN5A gene polymorphisms are associated with deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QT.
Daimi H., et al. Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice. Heart Rhythm. 2015, 12(6):1333-42. PubMed ID: 25701775

This article suggests microRNAs may be used to modulate Scn5a transcript bioavailability and thus to be used as putative therapeutic tools to regulate loss-of-function sodium channelopathies such as Brugada and/or gain-of-function sodium channelopathies such as long QT syndrome.
Park D.S., et al. Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. Journal of Clinical Investigation. 2015, 125(1):403-12. PubMed ID: 25500882

This article suggests that the SCN5A(E558X/+) pig model accurately reflects many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.
Juang J.M., et al. Unique clinical characteristics and SCN5A mutations in patients with Brugada syndrome in Taiwan. Journal of the Formosan Medical Association. 2015, 114(7):620-6. PubMed ID: 26154754

This article reveals that compared with Caucasian populations, the patients with BrS in Taiwan have some different clinical characteristics and low prevalence of SCN5A mutations.
Zhao Y., et al. Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p. Biochim Biophys Acta. 2015, 1852(10 Pt A):2024-34. PubMed ID: 26209011

This article suggests an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Nav1.5, reveals a novel role of miR-192-5p in cardiac physiology and disease, and provides a new target for novel miRNA-based antiarrhythmic therapy for diseases with reduced INa.

SCN5A Preparation Options

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Reference

Darbar D, et al. (2008). Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 117(15): 1927-35.

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