Understanding arrhythmogenesis by looking inside the cell

Abstract

c a k l i a In human ventricular myocardium, the cardiac delayedrectifier potassium current (IK) has two biophysically distinct components (IKr and IKs) and terminates repolarization together with the inward-rectifying current (IK1). The slow delayed-rectifier current (IKs) is an important ionic current roviding a component of the ventricular repolarization eserve. The native channel’s constituents (pore-forming -subunit KCNQ1 and modulatory -subunit KCNE1) asemble with presumably variable stoichiometry to generate unctional complexes with varying biophysical properties. Both delayed-rectifier components have been scrutinized with respect to modulation of synthesis, post-translational processing, trafficking, expression at the membrane, and channel degradation. Each of these processes needs to be functional to maintain a physiological steady state. Changes in the amount of IKs that is available for cardiomyocyte repolarization influence the propensity to arrhythmias in various cardiac conditions (genetically determined arrhythmia syndromes or acquired conditions). Membranes of cardiomyocytes are not immobile and static barriers—rather they represent highly regulated flexible systems with many important functions. After membrane proteins (like ion channels) have been synthesized in the endoplasmic reticulum, they often undergo post-translational modifications and are subsequently trafficked to the cell membrane where they are exposed to fulfill their functional role. In the case of ion channels, these functions directly relate to cellular excitability and repolarization. Malprocessed or malfunctioning proteins are degraded through internal quality control mechanisms before reaching the membrane. Once exposed to the cell exterior, proteins are again removed via endocytosis. Endocytosis is a tightly regulated, energy-consuming process that is crucial for the survival of eukaryotic cells. Clathrin-mediated enocytosis accounts for the greatest contribution to houseeeping or other specialized cellular functions and has so far een studied in the most detail. Adaptation of cells to nvironmental changes (e.g., electrical remodeling) dictates ubsequent alterations in membrane representations of ion hannel proteins. Classically, transcriptional, translational,