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


OBJECTIVE
We have tested the alterations of L-type calcium current (I(Ca)) and cardiac function in CaMKIIdelta knockout (KO) mouse left ventricle (LV).


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 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.


CONCLUSIONS
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.
Xu
Lin
L
Department of Pediatrics and Children's Healthcare of Atlanta, Emory University, GA, USA.
Lai
Dongwu
D
Cheng
Jun
J
Lim
Hyun Joung
HJ
Keskanokwong
Thitima
T
Backs
Johannes
J
Olson
Eric N
EN
Wang
Yanggan
Y
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D002118:Calcium / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency*; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D009929:Organ Size; D018487:Ventricular Dysfunction, Left / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
D020746:Calcium Channels, L-Type; D015124:8-Bromo Cyclic Adenosine Monophosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D002118:Calcium