SCN5A

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. SCN5A is a highly conserved gene 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. 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. 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. SCN5A is also expressed in the gastrointestinal tract. 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. NaV1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6).