Abstract
Ca/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) is the predominant isoform in the heart. During excitation-contraction coupling (ECC) CaMKII phosphorylates several Ca-handling proteins including ryanodine receptors (RyR), phospholamban, and L-type Ca channels. CaMKII expression and activity have been shown to correlate positively with impaired ejection fraction in the myocardium of patients with heart failure and CaMKII has been proposed to be a possible compensatory mechanism to keep hearts from complete failure. However, in addition to these acute effects on ECC, CaMKII was shown to be involved in hypertrophic signaling, termed excitation-transcription coupling (ETC). Thus, animal models have shown that overexpression of nuclear isoform CaMKIIdeltaB can induce myocyte hypertrophy. Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKIIdeltaC in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content. Interestingly, the frequency of diastolic spontaneous SR Ca release events (or opening of RyR) was greatly enhanced, demonstrating increased diastolic SR Ca leak. This was attributed to increased CaMKII-dependent RyR phosphorylation, resulting in increased and prolonged openings of RyR since Ca spark frequency could be reduced back to normal levels by CaMKII inhibition. This review focuses on acute and chronic effects of CaMKII in ECC and ETC. In summary, CaMKII overexpression can lead to heart failure and CaMKII-dependent RyR hyperphosphorylation seems to be a novel and important mechanism in ECC due to SR Ca leak which may be important in the pathogenesis of heart failure.
Highlights
Part of a talk presented at the XIX Annual Meeting of the Federação de Sociedades de Biologia Experimental, Águas de Lindóia, SP, Brazil, August 25-29, 2004
Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKIIδC in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content
calmodulin protein kinase II (CaMKII) overexpression can lead to heart failure and CaMKII-dependent ryanodine receptors (RyR) hyperphosphorylation seems to be a novel and important mechanism in excitation-contraction coupling (ECC) due to SR Ca leak which may be important in the pathogenesis of heart failure
Summary
Found, with δB being compartmentalized to the nucleus by means of an 11amino acid long nuclear localization sequence and with δC being the cytosolic isoform without nuclear localization sequence [4]. It is important to know that autophosphorylation itself is not essential for initial CaMKII activity, but does have important consequences, i.e., by increasing the affinity of the kinaseCaM complex [5] This effect traps Ca/CaM in the autophosphorylated subunit. During excitation-contraction coupling (ECC) Ca enters the cell mainly via voltagedependent L-type Ca channels (ICa), triggering Ca release from the sarcoplasmic reticulum (SR) via SR Ca channels (ryanodinereceptors, RyR), a process termed Ca-induced Ca release [14] These processes increase intracellular [Ca]i, causing Ca binding to troponin C which activates the myofilaments leading to contraction (systole). CaMKII can modulate ECC by phosphorylating several important Ca regulatory proteins in the heart in response to Ca signals, including RyR [15,16] and phospholamban (PLB; Refs. 17,18), and possibly L-type Ca channels [2], with multiple functional consequences
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