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.
Scn5a : sodium channel, voltage-gated, type V, alpha subunit
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 .
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. 
Nav1.5 protein co-localized with neurofilaments and clustered at a high
density in axons. 
Nav1.5 was originally identified as a cardiac sodium channel.
Subsequently, it was shown to be expressed in the brain at the mRNA level , , and these findings may explain whyNav1.5 mutations are associated with seizures. .
This isoform was not originally detected in brain, but more sensitive approaches have demonstrated expression in , ):
- Cerebral cortex
- Basal ganglia
- Olfactory system
- Limbic system: piriform cortex, septal nuclei, the diagonal band of Broca, amygdala, and habenular nuclei 
Nav1.5 is not observed in adult skeletal muscle, but it is detectable in neonatal skeletal muscle and after denervation of adult muscle .
Nav1.5 protein was localized in certain distinct regions of rat brain including the cerebral cortex, thalamus, hypothalamus, basalganglia, cerebellum and brain
The tetrodotoxin-insensitive Na+ channel expressed in human intestinal smooth muscle cells and interstitial cells of Cajal .
Cardiac muscle cells are resistant to nanomolar concentrations of TTX, and require micromolar concentrations for inhibition but are sensitive to inhibition by lidocaine .
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 .
Nav1.5 mutations are involved in the development of several diseases:
* Critical illness myopathy 
* Brugada syndrome (BrS)
* Cardiac conduction disease 
* Long QT syndrome (LQT3)
* Visceral pain 
* Arrhytmia 
And it is also implicated in the symthoms and/or evolution of:
* Human ovarian cancer 
* Breast cancer