CALMODULIN-DEPENDENT PROTEIN KINASE II IN HEART CALCIUM CHANNEL REGULATION

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Ca2+ entry through voltage-dependent Ca2+ channels is important in cardiac and vascular muscle excitation-contraction coupling. The Ca2+ regulated multifunctional protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII), has a very important role in signal transduction in nervous system, such as long-term potentiation (LTP) and memory. However, little i known as to whether this protein kinase also modulates the function of cardiac cells. Our studies demonstrate both spatially resolved and temporally distinct novel effects of CaMKII on L-type Ca2+ channel current (ICa) in cardiac cells. Either depolarization alone or calcium influx can increase the amplitude and slow the inactivation of ICa. The distinct volt e- and Ca2+-dependent effects persist with time constants of about 1.7 s and 9 s, respectively. Both effects are completely abolished by a specific peptide inhibitor of CaMKII. This CaMKII inhibitor also suppresses the prolongation of ICa induced by depolarizing holding potentials. An antibod specific for the autophosphorylated (activated) CaMKII, PY-66, is localized close to sarcolemmal membranes and the profile of CaMKII activation is qualitatively correlated with the changes in ICa under various conditions. Thus, the action of CaMKII on ICa is dually regulated by membrane depolarization and by calcium influx: the latter directly activates CaMKII while the former likely promotes the interaction between constitutive CaMKI and the membrane channel proteins. In contrast to the active CaMKII distribution, the intracellular distribution of the total CaMKII enzyme (visualized by using an antibody which specifically reacts with CaMKII k isoform) but does not sense its activation state is uniform with a higher nuclear distribution. This suggests that CaMKII is translocated to the cel sarcolemma following activation in cardiac myocytes. These findings provid new insights toward understanding the physiological function of the ubiquitous protein kinase, CaMKII in cardiac muscle cells as possibly in other type of cells as well.