期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 42, 期 1, 页码 196-205出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2006.09.007
关键词
calcium; CaMKII; L-type Ca2+ channel; sarcoplasmic reticulum; relaxation
资金
- NHLBI NIH HHS [P01 HL80101, P01 HL080101, R37 HL30077, R37 HL030077] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R37HL030077, P01HL080101] Funding Source: NIH RePORTER
Cardiac Ca2+/calmodulin-dependent Protein kinase II (CaMKII) in heart has been implicated in Ca2+ current (I-Ca) facilitation, enhanced sarcoplasmic reticulum (SR) Ca2+ release and frequency-dependent acceleration of relaxation (FDAR) via enhanced SR Ca2+ uptake. However, questions remain about how CaMKII may work in these three processes. Here we tested the role of CaMKII in these processes using transgenic mice (SR-AIP) that express four concatenated repeats of the CaNIKII inhibitory peptide AIP selectively in the SR membrane. Wild type mice (WT) and mice expressing AIP exclusively in the nucleus (NLS-AIP) served as controls. Increasing stimulation frequency produced typical FDAR in WT and NLS-AIP, but FDAR was markedly inhibited in SR-AIP. Quantitative analysis of cytosolic Ca2+ removal during [Ca2+](i) decline revealed that FDAR is due to an increased apparent V-max of SERCA. CaMKII-depenclent RyR phosphorylation at Ser2815 and SR Ca2+ leak was both decreased in SR-AIP vs. WT. This decrease in SR Ca2+ leak may partly balance the reduced SERCA activity leading to relatively unaltered SR-Ca2+ load in SR-AIP vs. WT myocytes. Surprisingly, CaNIKII regulation of the L-type Ca2+ channel (I-Ca facilitation and recovery from inactivation) was abolished by the SR-targeted CaMKII inhibition in SR-AIP mice. Inhibition of CaNIKII effects on ICa and RyR function by the SR-localized AIP places physical constraints on the localization of these proteins at the junctional microdomain. Thus SR-targeted CaNIKII inhibition can directly inhibit the activation of SR Ca2+ uptake, SR Ca2+ release and I-Ca, by CaMKII, effects which have all been implicated in triggered arrhythmias. (c) 2006 Elsevier Inc. All rights reserved.
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