Description: sodium channel, voltage-gated, type V, alpha subunit
Gene: Scn5a     Synonyms: nav1.5, scn5a

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The tetrodotoxin resistant channel Nav1.5, encoded by the gene SCN5A (also known as HB1; HB2; HH1; IVF; VF1; HBBD; ICCD; LQT3; SSS1; CDCD2; CMD1E; CMPD2; PFHB1; Nav1.5) is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene are a cause of long QT syndrome type 3 (LQT3), an autosomal dominant cardiac disease. Alternative splicing results in several transcript variants encoding different isoforms.



RGD ID Chromosome Position Species
3637 8 124446479-124545301 Rat
735253 9 119392529-119488134 Mouse
731255 3 38589553-38691164 Human

Scn5a : sodium channel, voltage-gated, type V, alpha subunit



Acc No Sequence Length Source
NM_001160162 n/A n/A NCBI
NM_013125 n/A n/A NCBI
NM_021544 n/A n/A NCBI
NM_198056 n/A n/A NCBI
NM_000335 n/A n/A NCBI
NM_001099405 n/A n/A NCBI
NM_001099404 n/A n/A NCBI
NM_001160160 n/A n/A NCBI
NM_001160161 n/A n/A NCBI



Accession Name Definition Evidence
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
GO:0001518 voltage-gated sodium channel complex A sodium channel in a cell membrane whose opening is governed by the membrane potential. IEA

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Nav1.5 is tetrodotoxin resistant. [332]



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The putative structure of Nav1.5 consists of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6). Interactions with the beta-subunits can also modulate fast inactivation, and the effects and the mechanisms that underlie these interactions are dependent on the specific alfa and beta-subunits involved. For example, the membrane anchor plus either the intracellular or the extracellular region of b1 is required to accelerate recovery from inactivation of Nav1.5. The b3 subunit also accelerates recovery from inactivation of Nav1.5 cardiac channels in oocytes, which may be physiologically significant because b3 is expressed in the ventricles and Purkinje fibers of the heart [1405].

In developmentally regulated D1:S3 splicing of Nav1.5, there are 31 nucleotide differences between the 50 -exon (‘neonatal’) and the 30 - exon (‘adult’) forms, resulting in 7 amino acid differences in D1:S3-S3/S4 linker. In particular, splicing replaces a conserved negative aspartate residue in the ‘adult’ with a positive lysine. [212]



Nav1.5 protein co-localized with neurofilaments and clustered at a high density in axons. [332]

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Nav1.5 was originally identified as a cardiac sodium channel. Subsequently, it was shown to be expressed in the brain at the mRNA level [843], [844], and these findings may explain whyNav1.5 mutations are associated with seizures. [332].

This isoform was not originally detected in brain, but more sensitive approaches have demonstrated expression in [834], [332]): - Cerebral cortex
- Thalamus
- Hypothalamus
- Basal ganglia
- Cerebellum
- Striatum
- Olfactory system
- Limbic system: piriform cortex, septal nuclei, the diagonal band of Broca, amygdala, and habenular nuclei [844]

Nav1.5 is not observed in adult skeletal muscle, but it is detectable in neonatal skeletal muscle and after denervation of adult muscle [834].

Nav1.5 protein was localized in certain distinct regions of rat brain including the cerebral cortex, thalamus, hypothalamus, basalganglia, cerebellum and brain stem. [332]

The tetrodotoxin-insensitive Na+ channel expressed in human intestinal smooth muscle cells and interstitial cells of Cajal [1413].

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Cardiac muscle cells are resistant to nanomolar concentrations of TTX, and require micromolar concentrations for inhibition but are sensitive to inhibition by lidocaine [834].

Fast inactivation in Nav1.5 can be modulated by the carboxyterminus of the channel and is slower when compared to Nav1.4 and Nav1.2 and this difference in kinetics is attributable to the first 100 amino acids in the carboxy-terminal region. These results are consistent with the fact that mutations in the carboxy-terminus of Nav1.5 that cause long QT syndrome disrupt fast inactivation. Deletion of the distal half of the carboxy-terminus did not affect activation or inactivation of NaV1.5, but a deletion starting with the sixth helical segment (which is highly charged) in the proximal half caused a marked increase in sustained current [1405].


Nav1.5 mutations are involved in the development of several diseases:
* Critical illness myopathy [1407]
* Brugada syndrome (BrS)[842]
* Cardiac conduction disease [841]
* Long QT syndrome (LQT3)[841]
* Visceral pain [1408]
* Arrhytmia [1409]

And it is also implicated in the symthoms and/or evolution of:
* Human ovarian cancer [830]
* Breast cancer [838]

Mouse models: Scn5a+/Delta (Brugada syndrome) [1410]
Scn5a+/- [1411]
Scn5a+/- [1412]







Wu L et al. Localization of Nav1.5 sodium channel protein in the mouse brain.
Neuroreport, 2002 Dec 20 , 13 (2547-51).


Tan HL et al. A sodium-channel mutation causes isolated cardiac conduction disease.
Nature, 2001 Feb 22 , 409 (1043-7).


Hartmann HA et al. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain.
Nat. Neurosci., 1999 Jul , 2 (593-5).

Cregg R et al. Pain Channelopathies.
, 2010 Feb 8 , ().

Papadatos GA et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.
Proc. Natl. Acad. Sci. U.S.A., 2002 Apr 30 , 99 (6210-5).



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