SCN5A and Nav1.5 Mutations in Regular and Irregular Cardiomyocyte Function and Arrhythmic Conduction Disorders

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In the heart, electrical conduction by gap junctions allows for the rapid and synchronous contraction of the heart by the net flux of K+, Ca2+, and Na+ ions1. These ions also enter cells through ion channels to initiate and propagate action potentials; the sodium ion channel is an integral part of this regulated process. Sodium channels are made of essential but varied subunits. For example, the Nav1.5 sodium ion channel, a major voltage gated channel in the heart, has an α-subunit that is coded for by the SCN5A gene2,3. Mutations to the SCN5A gene and its products result in mutated expression of the α-subunit and cause variance in channel inactivation speed and function4. This contributes to conditions such as long QT3 (LQT3), Brugada, …show more content…
It should be noted that these sodium channels are functional without β-subunits4. β1 to β4 subunits have been identified in the nine known subtypes of voltage gated sodium channels, Nav1.1 to Nav1.9, each with their corresponding α-subunit coded for by genes SCN1A to SCN11A that yield more than 50% homologous residues, according to Rook et al.2,4. Malhotra and colleagues propose that the two main β-subunits present in cardiac myocytes, β1 and β2, act in sodium current modulation (channel kinetics) and cell adhesion respectively7. Although Nav1.1, Nav1.3, and Nav1.6 are mainly expressed in cardiomyocyte T-tubules, Nav1.5 channels are present in cardiomyocyte membranes and are concentrated at intercalated discs; other sodium channels are known to be expressed around the body (such as in neurons and skeletal muscle)4. It should be noted that Nav1.5 distribution studies were done in a rat model, and therefore may not precisely reflect channel distribution in humans.
Nav1.5 α-Subunit
The α-subunit of the Nav1.5, which acts in forming the channel pore, consists of four homologous transmembrane domains (DI-DIV), each made of six segments, S1-S6 (Figure 1)2,4,8. Segment 4 of each domain is comprised of positively charged amino acids alternating with non-polar amino acids, serving as a voltage sensor2,4. Intracellular and extracellular links between intra-domain segments serve various purposes; notably, the extracellular

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