SCN5A

Last updated

SCN5A
Protein SCN5A PDB 1byy.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

6331

20271

Ensembl

ENSG00000183873

ENSMUSG00000032511

UniProt

Q14524

Q9JJV9

RefSeq (mRNA)

NM_001253860
NM_021544

RefSeq (protein)

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
View/Edit Human View/Edit Mouse

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) 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 NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

Contents

Gene structure

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 (NaV1.1, NaV1.2, NaV1.3, NaV1.6), neuronal channels (NaV1.7, NaV1.8 and NaV1.9), skeletal muscle channels (NaV1.4) and the cardiac sodium channel NaV1.5.

Expression pattern

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]

Splice variants

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]

Protein structure and function

NaV1.5 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]

NaV1.5 channels predominantly mediate the sodium current (INa) in cardiac cells. INa 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), NaV1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and NaV1.5 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 'INa,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]

Sub-units and protein interaction partners

Trafficking, function and structure of NaV1.5 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 NaV1.5, 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 NaV1.5. [13] Some of these have also been linked to genetic and acquired cardiac diseases. [14] [15]

Genetics

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. It is important to note that 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 NaV1.5 is generally reflected by an increase in INa,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]

SCN5A variations in the general population

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 NaV1.5 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]

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Brugada syndrome</span> Heart conduction disease

Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Short QT syndrome</span> Medical condition

Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature seen on an electrocardiogram (ECG) – a shortening of the QT interval. It is caused by mutations in genes encoding ion channels that shorten the cardiac action potential, and appears to be inherited in an autosomal dominant pattern. The condition is diagnosed using a 12-lead ECG. Short QT syndrome can be treated using an implantable cardioverter-defibrillator or medications including quinidine. Short QT syndrome was first described in 2000, and the first genetic mutation associated with the condition was identified in 2004.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

<span class="mw-page-title-main">Channelopathy</span> Diseases caused by disturbed function of ion channel subunits or the proteins that regulate them

Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes. Each type of channel is a multimeric complex of subunits encoded by a number of genes. Depending where the mutation occurs it may affect the gating, conductance, ion selectivity, or signal transduction of the channel.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

<span class="mw-page-title-main">Ajmaline</span> Chemical compound

Ajmaline is an alkaloid that is classified as a 1-A antiarrhythmic agent. It is often used to induce arrhythmic contraction in patients suspected of having Brugada syndrome. Individuals suffering from Brugada syndrome will be more susceptible to the arrhythmogenic effects of the drug, and this can be observed on an electrocardiogram as an ST elevation.

<span class="mw-page-title-main">Lorcainide</span> Antiarrythmic agent

Lorcainide is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac and Wolff–Parkinson–White syndrome. Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

<span class="mw-page-title-main">KCNE2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

An overlap syndrome is a medical condition which shares features of at least two more widely recognised disorders. Examples of overlap syndromes can be found in many medical specialties such as overlapping connective tissue disorders in rheumatology, and overlapping genetic disorders in cardiology.

<span class="mw-page-title-main">Plakophilin-2</span> Protein-coding gene in the species Homo sapiens

Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">SCN1B</span> Protein-coding gene in the species Homo sapiens

Sodium channel subunit beta-1 is a protein that in humans is encoded by the SCN1B gene.

<span class="mw-page-title-main">Ankyrin-2</span> Protein-coding gene in the species Homo sapiens

Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ANK2 cause a dominantly-inherited, cardiac arrhythmia syndrome known as long QT syndrome 4 as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-2 expression levels are observed in human heart failure.

Na<sub>v</sub>1.8 Protein-coding gene in the species Homo sapiens

Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.

<span class="mw-page-title-main">Ankyrin-3</span> Protein-coding gene in the species Homo sapiens

Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.

GPD1L is a human gene. The protein encoded by this gene contains a glycerol-3-phosphate dehydrogenase (NAD+) motif and shares 72% sequence identity with GPD1.

<span class="mw-page-title-main">KCNE5</span> Protein-coding gene in the species Homo sapiens

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.

<span class="mw-page-title-main">Sudden arrhythmic death syndrome</span> Medical condition

Sudden arrhythmic death syndrome (SADS) is a sudden unexpected death of adolescents and adults, mainly during sleep. One relatively common type is known as Brugada syndrome.

References

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  23. 1 2 Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Robinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Mérot J, Turpault R, Coudière Y, Charpentier F, Schott JJ, Loussouarn G, Wilde AA, Wolf JE, Baró I, Kyndt F, Probst V (July 2012). "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". Journal of the American College of Cardiology. 60 (2): 144–56. doi: 10.1016/j.jacc.2012.02.052 . PMID   22766342.
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  25. ↑ Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, Ohno S, Nishio Y, Tsuji K, Itoh H, Kimura T, Kita T, Horie M (October 2008). "A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation". Journal of the American College of Cardiology. 52 (16): 1326–34. doi: 10.1016/j.jacc.2008.07.013 . PMID   18929244.
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  27. ↑ Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah R, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D (October 2012). "R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy". Journal of the American College of Cardiology. 60 (16): 1566–73. doi: 10.1016/j.jacc.2012.05.050 . PMID   22999724.
  28. ↑ Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (January 2005). "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation". JAMA. 293 (4): 447–54. doi:10.1001/jama.293.4.447. PMC   2039897 . PMID   15671429.
  29. ↑ Verstraelen TE, Ter Bekke RM, Volders PG, Masclee AA, Kruimel JW (2015). "The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders". Neurogastroenterology & Motility. 27 (7): 906–13. doi:10.1111/nmo.12569. PMID   25898860. S2CID   5055360.
  30. ↑ Beyder A, Mazzone A, Strege PR, Tester DJ, Saito YA, Bernard CE, Enders FT, Ek WE, Schmidt PT, Dlugosz A, Lindberg G, Karling P, Ohlsson B, Gazouli M, Nardone G, Cuomo R, Usai-Satta P, Galeazzi F, Neri M, Portincasa P, Bellini M, Barbara G, Camilleri M, Locke GR, Talley NJ, D'Amato M, Ackerman MJ, Farrugia G (June 2014). "Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome". Gastroenterology. 146 (7): 1659–68. doi:10.1053/j.gastro.2014.02.054. PMC   4096335 . PMID   24613995.
  31. ↑ Beyder A, Strege PR, Bernard CE, Mazzone A, Tester DJ, Saito YA, Camilleri M, Locke GR, Talley NJ (1 September 2013). "Mexiletine rescues dysfunction of the Nav1.5 mutation A997t and restores bowel function in a patient with irritable bowel syndrome (ibs)". Neurogastroenterology & Motility. 25. ISSN   1350-1925.
  32. ↑ Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (February 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". European Heart Journal. 5 (2): 99–107. doi:10.1093/oxfordjournals.eurheartj.a061633. PMID   6723689.
  33. 1 2 Balser JR (April 2001). "The cardiac sodium channel: gating function and molecular pharmacology". Journal of Molecular and Cellular Cardiology. 33 (4): 599–613. doi:10.1006/jmcc.2000.1346. PMID   11273715. S2CID   35893248.

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