DUAL REGULATION OF CA2+/CALMODULIN-DEPENDENT KINASE-II ACTIVITY BY MEMBRANE VOLTAGE AND BY CALCIUM INFLUX

Calcium entry through voltage-gated Ca2+ channels is critical in cardiac excitation-contraction coupling and calcium metabolism. In this report, we demonstrate both spatially resolved and temporally distinct effects of Ca2+/ calmodulin-dependent protein kinase II (CaMKII) on L-type Ca2+ channel current (I-Ca) in rat cardiac myocytes. Either depolarization alone or calcium influx can increase the amplitude and slow the inactivation of I-Ca. The distinct voltage- and Ca2+-dependent effects persist with time constants of approximate to 1.7 sec and 9 sec, respectively. Both effects are completely abolished by a specific peptide inhibitor of CaMKII. This CaMKII inhibitor also suppresses the prolongation of I-Ca induced by depolarizing holding potentials. Furthermore, using an antibody specific for the autophosphorylated (activated) CaMKII, we find that this kinase is localized close to sarcolemmal membranes and that the profile of CaMKII activation correlates qualitatively with the changes in I-Ca under various conditions. Therefore, we conclude that the action of CaMKII on I-Ca is dually regulated by membrane depolarization and by Ca2+ influx; the latter directly activates CaMKII, whereas the former likely promotes the interaction between constitutive CaMKII and the membrane-channel proteins. These regulatory mechanisms provide positive-feedback control of Ca2+ channels and are probably important in the regulation of cardiac contractility and other intracellular Ca2+-regulated processes.