SCN5A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KBI, 2L53, 4DCK, 4DJC, 4JQ0, 4OVN
Identifiers
Aliases	SCN5A, CDCD2, CMD1E, CMPD2, HB1, HB2, HBBD, HH1, ICCD, IVF, LQT3, Nav1.5, PFHB1, SSS1, VF1, sodium voltage-gated channel alpha subunit 5
External IDs	OMIM: 600163; MGI: 98251; HomoloGene: 22738; GeneCards: SCN5A; OMA:SCN5A - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p22.2 Start 38,548,057 bp[1] End 38,649,687 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F3|9 71.33 cM Start 119,312,474 bp[2] End 119,408,082 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart left ventricle right auricle myocardium of left ventricle right ventricle cardiac muscle tissue of right atrium testicle gonad secondary oocyte sural nerve Top expressed in myocardium of ventricle atrium Meckel's cartilage right ventricle rib olfactory epithelium scapula cardiac muscles atrioventricular valve endothelial cell of lymphatic vessel More reference expression data BioGPS n/a
Gene ontology Molecular function nitric-oxide synthase binding transmembrane transporter binding protein domain specific binding voltage-gated sodium channel activity involved in AV node cell action potential voltage-gated sodium channel activity involved in bundle of His cell action potential sodium channel activity voltage-gated sodium channel activity involved in SA node cell action potential voltage-gated ion channel activity ion channel activity voltage-gated sodium channel activity involved in Purkinje myocyte action potential protein binding ankyrin binding enzyme binding fibroblast growth factor binding voltage-gated sodium channel activity involved in cardiac muscle cell action potential scaffold protein binding protein kinase binding ubiquitin protein ligase binding voltage-gated sodium channel activity calmodulin binding Cellular component voltage-gated sodium channel complex integral component of membrane lateral plasma membrane membrane intercalated disc T-tubule intracellular anatomical structure cell surface Z discdkac endoplasmic reticulum caveola sarcolemma plasma membrane cytoplasm perinuclear region of cytoplasm axon Biological process regulation of atrial cardiac muscle cell membrane repolarization cellular response to calcium ion membrane depolarization during AV node cell action potential regulation of ventricular cardiac muscle cell membrane depolarization membrane depolarization during Purkinje myocyte cell action potential membrane depolarization during bundle of His cell action potential membrane depolarization during action potential cardiac muscle contraction sodium ion transmembrane transport sodium ion transport positive regulation of epithelial cell proliferation SA node cell action potential brainstem development cardiac ventricle development regulation of atrial cardiac muscle cell membrane depolarization membrane depolarization ventricular cardiac muscle cell action potential bundle of His cell action potential cardiac muscle cell action potential involved in contraction regulation of ion transmembrane transport ion transport cerebellum development regulation of heart rate odontogenesis of dentin-containing tooth positive regulation of action potential regulation of cardiac muscle cell contraction telencephalon development AV node cell to bundle of His cell communication transmembrane transport positive regulation of sodium ion transport membrane depolarization during SA node cell action potential response to denervation involved in regulation of muscle adaptation regulation of sodium ion transmembrane transport AV node cell action potential regulation of heart rate by cardiac conduction membrane depolarization during cardiac muscle cell action potential neuronal action potential regulation of ventricular cardiac muscle cell membrane repolarization atrial cardiac muscle cell action potential membrane depolarization during atrial cardiac muscle cell action potential cardiac conduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6331 20271 Ensembl ENSG00000183873 ENSMUSG00000032511 UniProt Q14524 Q9JJV9 RefSeq (mRNA) NM_000335 NM_001099404 NM_001099405 NM_001160160 NM_001160161 NM_198056 NM_001354701 NM_001253860 NM_021544 RefSeq (protein) NP_000326 NP_001092874 NP_001092875 NP_001153632 NP_001153633 NP_932173 NP_001341630 NP_001240789 NP_067519 Location (UCSC) Chr 3: 38.55 – 38.65 Mb Chr 9: 119.31 – 119.41 Mb PubMed search [3] [4]
Wikidata
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Sodium channel protein type 5 subunit alpha, also known as Na_V1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. Na_V1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na⁺-ions (I_Na) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in Na_V1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel Na_V1.5.

SCN5A is a highly conserved gene^[5] located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28 exons, of which exon 1 and in part exon 2 form the 5' untranslated region (5’UTR) and exon 28 the 3' untranslated region (3’UTR) of the RNA. SCN5A is part of a family of 10 genes that encode different types of sodium channels, i.e. brain-type (Na_V1.1, Na_V1.2, Na_V1.3, Na_V1.6), neuronal channels (Na_V1.7, Na_V1.8 and Na_V1.9), skeletal muscle channels (Na_V1.4) and the cardiac sodium channel Na_V1.5.

SCN5A is mainly expressed in the heart, where expression is abundant in working myocardium and conduction tissue. In contrast, expression is low in the sinoatrial node and atrioventricular node.^[6] Within the heart, a transmural expression gradient from subendocardium to subsepicardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium.^[6] SCN5A is also expressed in the gastrointestinal tract.^[7]

More than 10 different splice isoforms have been described for SCN5A, of which several harbour different functional properties. In the heart, two isoforms are mainly expressed (ratio 1:2), of which the least predominant one contains an extra glutamine at position 1077 (1077Q). Moreover, different isoforms are expressed during fetal life and adult, differing in the inclusion of an alternative exon 6.^[8]

Na_V1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6). The pore region of the channels, through which Na+-ions flow, are formed by the segments S5 and S6 of the 4 domains. Voltage sensing is mediated by the remaining segments, of which the positively charged S4 segments plays a fundamental role.^[5][9]

Na_V1.5 channels predominantly mediate the sodium current (I_Na) in cardiac cells. I_Na is responsible for the fast upstroke of the action potential, and as such plays a crucial role in impulse propagation through the heart. The conformational state of the channel, which is both voltage and time-dependent, determines whether the channel is opened or closed. At the resting membrane potential (around -85 mV), Na_V1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and Na_V1.5 channels open through the outward movement of the S4 segments, leading to the initiation of the action potential. Simultaneously, a process called 'fast inactivation' results in closure of the channels within a few milliseconds. In physiological conditions, when inactivated, channels remain in closed state until the cell membrane repolarizes, where a recovery from inactivation is necessary before they become available for activation again. During the action potential, a very small fraction of sodium current persists and does not inactivate completely. This current is called 'sustained current', 'late current' or 'I_Na,L’.^[10][11] Also, some channels may reactivate during the repolarizing phase of the action potential at a range of potentials where inactivation is not complete and shows overlap with activation, generating the so-called "window current".^[12]

Trafficking, function and structure of Na_V1.5 can be affected by the many protein interaction partners that have been identified to date (for an extensive review, see Abriel et al. 2010).^[13] Of these, the 4 sodium channel beta-subunits, encoded by the genes SCN1B, SCN2B, SCN3B and SCN4B, form an important category. In general, beta-subunits increase function of Na_V1.5, either by change in intrinsic properties or by affecting the process of trafficking to the cell surface.

Apart from the beta-subunits, other proteins, such as calmodulin, calmodulin kinase II δc, ankyrin-G and plakophilin-2, are known to interact and modulate function of Na_V1.5.^[13] Some of these have also been linked to genetic and acquired cardiac diseases.^[14][15]

Mutations in SCN5A, which could result in a loss and/or a gain-of-function of the channel, are associated with a spectrum of cardiac diseases. Pathogenic mutations generally exhibit an autosomal dominant inheritance pattern, although compound heterozygote forms of SCN5A mutations are also described. Also, mutations may act as a disease modifier, especially in families where lack of direct causality is reflected by complex inheritance patterns. A significant number of individuals (2-7%) in the general population carry a rare (population frequency <1%),^[16] protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. Mutations that result in the same biophysical effect can give rise to different diseases.

To date, loss-of-function mutations have been associated with Brugada syndrome (BrS),^[17][18][19] progressive cardiac conduction disease (Lev-Lenègre disease),^[20][21] dilated cardiomyopathy (DCM),^[22][23] sick sinus syndrome,^[24] and atrial fibrillation.^[25]

Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3^[19][26] and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC)^[23][27] Some gain-of-function mutations are also associated with AF and DCM.^[28] Gain-of-function of Na_V1.5 is generally reflected by an increase in I_Na,L, a slowed rate of inactivation or a shift in voltage dependence of activation or inactivation (resulting in an increased window-current).

SCN5A mutations are believed to be found in a disproportionate number of people who have Irritable Bowel Syndrome, particularly the constipation-predominant variant (IBS-C).^[7][29] The resulting defect leads to disruption in bowel function, by affecting the Nav1.5 channel, in smooth muscle of the colon and pacemaker cells.^[7] Researchers managed to treat a case of IBS-C with mexiletine to restore Nav1.5 channels, reversing constipation and abdominal pain.^{[30][unreliable medical source][31]}

Genetic variations in SCN5A, i.e. single nucleotide polymorphisms (SNPs) have been described in both coding and non-coding regions of the gene. These variations are typically present at relatively high frequencies within the general population. Genome Wide Association Studies (GWAS) have used this type of common genetic variation to identify genetic loci associated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detect loci involved in variation in electrocardiographic parameters (i.e. PR-, QRS- and QTc-interval duration) in the general population.^[16] The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. these studies consistently identified the SCN5A-SCN10A genomic region on chromosome 3 to be associated with variation in QTc-interval, QRS duration and PR-interval.^[16] These results indicate that genetic variation at the SCN5A locus is not only involved in disease genetics but also plays a role in the variation in cardiac function between individuals in the general population.

The cardiac sodium channel Na_V1.5 has long been a common target in the pharmacologic treatment of arrhythmic events. Classically, sodium channel blockers that block the peak sodium current are classified as Class I anti-arrhythmic agents and further subdivided in class IA, IB and IC, depending on their ability to change the length of the cardiac action potential.^[32][33] Use of such sodium channel blockers is among others indicated in patients with ventricular reentrant tachyarrhythmia in the setting of cardiac ischemia and in patients with atrial fibrillation in absence of structural heart disease.^[33]

• Atrioventricular block
• Brugada syndrome
• Electrical conduction system of the heart
• Electrocardiogram (ECG)
• First-degree AV block
• long QT syndrome
• Second-degree AV block
• Sodium channel

The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Christiaan C Veerman, Arthur A M Wilde, Elisabeth M Lodder (8 September 2015). "The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology". Gene. Gene Wiki Review Series. 573 (2): 177–187. doi:10.1016/J.GENE.2015.08.062. ISSN 0378-1119. PMC 6636349. PMID 26361848. Wikidata Q38585131.

• GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
• GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
• SCN5A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: Q14524 (Sodium channel protein type 5 subunit alpha) at the PDBe-KB.