Alterations of L-type calcium current and cardiac function in CaMKII δ 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 CaMKIIδ knockout (KO) mouse left ventricle (LV). Methods and Results: We used the patch-clamp method to record I_Cain ventricular myocytes and found that in KO LV, basal I _Cawas significantly increased without changing the transmural gradient of I_Cadistribution. Substitution of Ba²⁺for Ca²⁺showed similar increase in IBa. There was no change in the voltage dependence of I_Caactivation and inactivation. I _Carecovery from inactivation, however, was significantly slowed. In KO LV, the Ca²⁺-dependent I_Cafacilitation (CDF) and I _Caresponse to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by β2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in β1-AR and an increase in Ca_v1.2, β2-AR, and Gαi3 protein levels. Ca ²⁺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 β-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or β-adrenergic stimulation. Conclusions: Our results implicate physiological CaMKII activity in maintaining normal I_Ca, Ca²⁺handling, excitationcontraction coupling, and the in vivo heart function in response to cardiac stress.