New insights into the complex effects of KChIP2 on calcium transients

摘要

the initial phase of cardiac repolarization (phase 1 in humans) is mediated by the transient outward K~+ current (I_(to)). I_(to) is composed of the Ca~(2+)-independent K~+ current (I_(to1)) and a Ca~(2+)-activated chloride current (I_(to2)), both of which are voltage dependent (3). I_(to1) is further subdivided into fast (I_(to,f)) and slow (I_(to,s)) (3). I_(to,f) is mediated by Kv4 channels that form complexes with K~+ channel-interacting protein 2 (KChIP2) proteins in the majority of cardiomyocytes. Kv4 is the pore-forming unit, and KChIP2 is an accessory K~+ channel-interacting protein residing on the cytoplasmic side (10, 12). The discovery of KChIP2 proteins in neurons (1) led to the generation of knockout mouse models of KChIP2 to study the role of this protein in cardiac electrophysiology through loss of function (9). Removal of KChIP2 in mice leads to disappearance of I_(to,f). More recently, it was discovered that KChIP2 proteins also bind to Ca_v1.2, which is responsible for the L-type Ca~(2+) current (I_(Ca,L)) (15). In KChIP2~(-/-) mouse cardiomyocytes, I_(Ca,L) is reduced but Cav1.2 protein levels are unchanged (15). Therefore, KChIP2 proteins are capable of modulating various ionic currents that determine the action potential plateau and regulate contractility.