Alterations of L-Type Calcium Current and Cardiac Function in CaMKIIδ Knockout Mice

Rationale: Recent studies have highlighted important roles of CaMKII in regulating Ca2+ handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood. Objective: We have tested the alterations of L-type calcium current (I-Ca) and cardiac function in CaMKII delta knockout (KO) mouse left ventricle (LV). Methods and Results: We used the patch-clamp method to record I-Ca in ventricular myocytes and found that in KO LV, basal I-Ca was significantly increased without changing the transmural gradient of I-Ca distribution. Substitution of Ba2+ for Ca2+ showed similar increase in I-Ba. There was no change in the voltage dependence of I-Ca activation and inactivation. I-Ca recovery from inactivation, however, was significantly slowed. In KO LV, the Ca2+-dependent I-Ca facilitation (CDF) and I-Ca response to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by beta 2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in beta 1-AR and an increase in Ca(v)1.2, beta 2-AR, and G alpha i3 protein levels. Ca2+ transient and sarcomere shortening in KO myocytes were unchanged at 1-Hz but reduced at 3-Hz stimulation. Echocardiography in conscious mice revealed an increased basal contractility in KO mice. However, cardiac reserve to work load and beta-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or beta-adrenergic stimulation. Conclusions: Our results implicate physiological CaMKII activity in maintaining normal I-Ca, Ca2+ handling, excitation-contraction coupling, and the in vivo heart function in response to cardiac stress. (Circ Res. 2010;107:398-407.)