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

• Published in: Circulation research Vol. 107; no. 3; pp. 398 - 407
• Main Authors: Xu, Lin, Lai, Dongwu, Cheng, Jun, Lim, Hyun Joung, Keskanokwong, Thitima, Backs, Johannes, Olson, Eric N, Wang, Yanggan
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 06.08.2010; Lippincott Williams & Wilkins
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system; calcium channel; calmodulin-dependent protein kinase; Calcium; Excitation contraction coupling; Enzyme; Transferases; Rodentia; Alteration; Ionic channel; Ionic current; Inorganic element; myocytes; Myocyte; Vertebrata; Mammalia; CaMKII; Mouse; Circulatory system; Mutation; excitation-contraction coupling; Ca
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.222562

RATIONALERecent studies have highlighted important roles of CaMKII in regulating Ca handling and excitation-contraction coupling. However, the cardiac effect of chronic CaMKII inhibition has not been well understood. OBJECTIVEWe have tested the alterations of L-type calcium current (ICa) and cardiac function in CaMKIIδ knockout (KO) mouse left ventricle (LV). METHODS AND RESULTSWe used the patch-clamp method to record ICa in ventricular myocytes and found that in KO LV, basal ICa was significantly increased without changing the transmural gradient of ICa distribution. Substitution of Ba for Ca showed similar increase in IBa. There was no change in the voltage dependence of ICa activation and inactivation. ICa recovery from inactivation, however, was significantly slowed. In KO LV, the Ca-dependent ICa facilitation (CDF) and ICa response 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 Cav1.2, β2-AR, and Gαi3 protein levels. Ca 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. CONCLUSIONSOur results implicate physiological CaMKII activity in maintaining normal ICa, Ca handling, excitation-contraction coupling, and the in vivo heart function in response to cardiac stress.