SCN5A, Nav1.5, and the Underlying Molecular Mechanisms of SCN5A Mutations in Disease
Molecular structure of the SCN5A transcript with its 28 exons, which is translated into the α-subunit (Nav1.5) of the cardiac sodium channel. Nav1.5 consists of an N-terminus, C-terminus, and 4 structurally homologous domains (DI to DIV). Each domain contains 6 transmembrane segments (S1 to S6). The 4 domains fold to form an ion-conducting pore. At the cell membrane, Nav1.5 interacts with β-subunits and other regulatory proteins. Mechanisms by which SCN5A mutations cause Nav1.5 loss-of-function and gain-of-function involve disruptions in several molecular process including gene transcription and translation, Nav1.5 folding and trafficking, and Nav1.5 interaction with the regulatory proteins. In addition, SCN5A mutations may cause changes in channel gating. Loss-of-function effects on gating involve activation of Nav1.5 channels at more depolarized membrane potentials (left upper inset) or inactivation at less depolarized potentials (left lower inset). Gain-of-function effects on gating include an increase in the late sodium current (green area in right upper inset) due to incomplete inactivation of Nav1.5 channels or increase in the window current (green area in right lower inset) due to later inactivation of the channels at more depolarized potentials.