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Alterations of L-type calcium current and cardiac function in CaMKII{delta} knockout mice.


ABSTRACT: Recent studies have highlighted important roles of CaMKII in regulating Ca(2+) handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood.We have tested the alterations of L-type calcium current (I(Ca)) and cardiac function in CaMKIIdelta knockout (KO) mouse left ventricle (LV).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 Ba(2+) for Ca(2+) 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 Ca(2+)-dependent I(Ca) facilitation (CDF) and I(Ca) response to isoproterenol (ISO) were significantly reduced. However, ISO response was reversed by beta2-adrenergic receptor (AR) inhibition. Western blots showed a decrease in beta1-AR and an increase in Ca(v)1.2, beta2-AR, and Galphai3 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 beta-adrenergic stimulation was reduced. Surprisingly, KO mice showed a reduced heart rate in response to work load or beta-adrenergic stimulation.Our results implicate physiological CaMKII activity in maintaining normal I(Ca), Ca(2+) handling, excitation-contraction coupling, and the in vivo heart function in response to cardiac stress.

SUBMITTER: Xu L 

PROVIDER: S-EPMC2923749 | BioStudies | 2010-01-01

REPOSITORIES: biostudies

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