Sodium channel protein type 5 subunit alpha

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Reviewed, UniProtKB/Swiss-Prot Q14524 (SCN5A_HUMAN)

Last modified June 16, 2009. Version 105. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Sodium channel protein type 5 subunit alpha
Alternative name(s):
    Sodium channel protein type V subunit alpha
    Voltage-gated sodium channel subunit alpha Nav1.5
    Sodium channel protein cardiac muscle subunit alpha
    HH1

Gene names

Name:

SCN5A

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	2016 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na⁺ ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na⁺ channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram.
Subunit structure	Interacts with the PDZ domain of the syntrophin SNTA1, SNTB1 and SNTB2 By similarity. Interacts with NEDD4, NEDD4L and WWP2.
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Found in jejunal circular smooth muscle cells (at protein level). Expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. Isoform 4 is expressed in brain.
Domain	The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1,S2,S3,S5,S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.
Post-translational modification	Ubiquitinated by NEDD4L; which promotes its endocytosis. Does not seem to be ubiquitinated by NEDD4 or WWP2. Ref.10 Ref.11
Involvement in disease	Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:113900]; also known as Lenegre-Lev disease or progressive cardiac conduction defect (PCCD). PFHB1A is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. PFHB1A is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrio-ventricular block and causing syncope and sudden death. Ref.28 Ref.39 Ref.51 Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM:603830]. Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT3 inheritance is an autosomal dominant. Ref.28 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.12 Ref.23 Ref.25 Ref.27 Ref.30 Ref.32 Ref.34 Ref.36 Ref.40 Ref.42 Ref.50 Ref.61 Defects in SCN5A are the cause of Brugada syndrome (BRS1) [MIM:601144]. BRS1 is an autosomal dominant tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset. Ref.28 Ref.34 Ref.22 Ref.24 Ref.26 Ref.29 Ref.38 Ref.41 Ref.43 Ref.45 Ref.55 Ref.56 Ref.57 Ref.59 Ref.60 Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM:608567]. The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder. Ref.28 Ref.35 Ref.52 Defects in SCN5A are a cause of idiopathic ventricular fibrillation (IVF) [MIM:603829]; also called paroxysmal familial ventricular fibrillation. IVF is a self originated, of unknown causation, ventricular fibrillation that causes the ventricles to beat so fast that they can prevent the blood from circulating efficiently in the body. This disorder is not truly idiopathic in many cases but can be caused by specific mutations such as those in the SCN5A gene. IVF is said to cause more than 300,000 sudden deaths each year in the United States alone. In approximately 5 to 12% of cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation. Ref.28 Ref.31 Defects in SCN5A can be a cause of sudden infant death syndrome (SIDS) [MIM:272120]. SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Long QT syndromes-associated mutations can be responsible for some of SIDS cases. Ref.28 Defects in SCN5A may be a cause of familial atrial standstill [MIM:108770]. Atrial standstill is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. Ref.28 Ref.48 Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM:601154]; also known as dilated cardiomyopathy with conduction disorder and arrhythmia or dilated cardiomyopathy with conduction defect 2. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Ref.28 Ref.54
Miscellaneous	Na⁺ channels in mammalian cardiac membrane have functional properties quite distinct from Na⁺ channels in nerve and skeletal muscle.
Sequence similarities	Belongs to the sodium channel family. Contains 1 IQ domain.

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Ontologies

Keywords
Biological process	Ion transport Sodium transport Transport
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Brugada syndrome Cardiomyopathy Disease mutation Long QT syndrome
Domain	Repeat Transmembrane
Ligand	Sodium
Molecular function	Ionic channel Sodium channel Voltage-gated channel
PTM	Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	blood circulation Ref.15 Non-traceable author statement. Source: ProtInc muscle contraction Ref.15 Traceable author statement. Source: ProtInc regulation of heart contraction Ref.22 Traceable author statement. Source: ProtInc sodium ion transport Ref.17 Traceable author statement. Source: ProtInc
Cellular component	voltage-gated sodium channel complex Inferred from electronic annotation. Source: InterPro
Molecular function	protein binding Inferred from physical interaction. Source: UniProtKB sodium ion binding Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated sodium channel activity Ref.17 Traceable author statement. Source: ProtInc
Complete GO annotation...

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Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q14524-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q14524-2) The sequence of this isoform differs from the canonical sequence as follows: 1076-1076: Missing.
Note: Very abundant isoform.

Isoform 3 (identifier: Q14524-3) The sequence of this isoform differs from the canonical sequence as follows: 206-211: TTEFVD → VSENIK 1076-1076: Missing. 1573-1604: Missing.

Isoform 4 (identifier: Q14524-4) The sequence of this isoform differs from the canonical sequence as follows: 206-211: TTEFVD → VSENIK

Isoform 5 (identifier: Q14524-5) The sequence of this isoform differs from the canonical sequence as follows: 206-211: TTEFVD → VSENIK 1077-1130: Missing.

Isoform 6 (identifier: Q14524-6) The sequence of this isoform differs from the canonical sequence as follows: 206-211: TTEFVD → VSENIK 1416-1433: Missing.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 2016

2016

Sodium channel protein type 5 subunit alpha

PRO_0000048497

Regions

Transmembrane

127 – 150

S1 of repeat I Potential

Transmembrane

159 – 178

S2 of repeat I Potential

Transmembrane

192 – 210

S3 of repeat I Potential

Transmembrane

217 – 236

S4 of repeat I Potential

Transmembrane

253 – 276

S5 of repeat I Potential

Transmembrane

390 – 415

S6 of repeat I Potential

Transmembrane

712 – 736

S1 of repeat II Potential

Transmembrane

748 – 771

S2 of repeat II Potential

Transmembrane

780 – 799

S3 of repeat II Potential

Transmembrane

806 – 825

S4 of repeat II Potential

Transmembrane

842 – 862

S5 of repeat II Potential

Transmembrane

914 – 939

S6 of repeat II Potential

Transmembrane

1201 – 1224

S1 of repeat III Potential

Transmembrane

1238 – 1263

S2 of repeat III Potential

Transmembrane

1270 – 1291

S3 of repeat III Potential

Transmembrane

1296 – 1317

S4 of repeat III Potential

Transmembrane

1337 – 1359

S5 of repeat III Potential

Transmembrane

1444 – 1470

S6 of repeat III Potential

Transmembrane

1524 – 1547

S1 of repeat IV Potential

Transmembrane

1559 – 1582

S2 of repeat IV Potential

Transmembrane

1589 – 1612

S3 of repeat IV Potential

Transmembrane

1623 – 1644

S4 of repeat IV Potential

Transmembrane

1660 – 1682

S5 of repeat IV Potential

Transmembrane

1748 – 1772

S6 of repeat IV Potential

Domain

1901 – 1930

Region

1974 – 1977

Interaction with NEDD4, NEDD4L and WWP2