Connexin 43 and CaV1.2 Ion Channel Trafficking in Healthy and Diseased Myocardium.

Abstract

A remarkable aspect of cardiac ion channel biology is that individual ion channels have half-lives on the order of hours. For example, Connexin 43 (Cx43) gap junction proteins have a half-life of 1 to 3 hours,1,2 whereas potassium channels, calcium channels, and the sodium–calcium exchanger have half-lives that are reported in the 2 to 8 hours range.3–6 The short life span of ion channels suggests that there needs to be efficiency in their life cycle and movements which follow the order of: formation, delivery to the correct subdomain on plasma membrane, behavior once in membrane, and internalization back into the cell. To maintain this efficiency in ion trafficking, thousands of individual proteins contribute to a functional equilibrium. Mutations in a single protein can disrupt this equilibrium and over time manifest as arrhythmogenic substrate or cardiomyopathy. Cardiomyocytes use common intracellular organelles and machinery to produce and shuttle ion channel proteins to their specific organelles and functional subdomains at the cell membrane. After gene transcription in the nuclei, proteins are translated and subjected to post-translational modification in the endoplasmic reticulum (ER) and then further modified in the Golgi apparatus. For ion channels, sorting and delivery to their subcellular destination begins in the Golgi apparatus. The Golgi complex is usually found adjacent to the lateral side of each nucleus in mammalian ventricular cardiomyocytes. Co-localized with each Golgi is the centrosome at which microtubules are nucleated and extend throughout the cell.7 Sorting of proteins mainly takes place at the trans-Golgi network (TGN).8 Cargo proteins are sorted into post-Golgi carriers, which are docked onto molecular motors and delivered to the cell periphery along microtubules.9 These extending microtubules form an intricate and dynamic outgoing network capable of shuttling ion channel–containing vesicles to their destinations. In the context …