© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure
Department of Pharmacology 0636, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
* Corresponding author. Tel.: +1-858-534-2595; fax: +1-858-534-4337. Email address: jhbrown{at}ucsd.edu
Ca2+/calmodulin-dependent protein kinase II (CaMKII), a critical transducer of Ca2+ signaling, is a multifunctional protein kinase which can phosphorylate a wide range of substrates and regulate numerous cellular functions. The 
isoforms of CaMKII predominate in the heart and two splice variants of CaMKII, B and C, have been demonstrated to be present in the adult mammalian myocardium. The B isoform contains a nuclear localization signal (NLS) that is absent from C, and consequently, the two isoforms have different subcellular localization. Recent work from our laboratory and others has implicated CaMKII in the development of cardiac hypertrophy and heart failure. The specific roles of these CaMKII isoforms in regulating cardiac function appear to be determined by their subcellular localization. The nuclear B isoform plays a key role in hypertrophic gene expression, whereas the cytoplasmic C isoform can affect excitation–contraction (E–C) coupling through phosphorylation of Ca2+ regulatory proteins and may also transduce signals leading to apoptosis. In addition, the nuclear B and the cytoplasmic C isoforms of CaMKII are differentially regulated in pressure overload-induced cardiac hypertrophy. This review focuses on evidence that CaMKII plays an essential role in transcriptional activation associated with cardiac hypertrophy, as well as the aberrant Ca2+ handling and apoptosis that may contribute to heart failure. The hypothesis that CaMKII isoform selective activation, localization and substrate phosphorylation lead to specificity in the resultant signaling pathways is discussed.
KEYWORDS Ca2+/calmodulin-dependent protein kinase II; Cardiac hypertrophy; Gene expression; Heart failure; E–C coupling
Time for primary review 19 days
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