Copyright © 2007, European Society of Cardiology
Calmodulin and Ca2+/calmodulin kinases in the heart – Physiology and pathophysiology
aDepartment of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
bDepartment of Physiology, Loyola University Chicago, IL, USA
cDepartment of Pharmacology, UCSD, CA, USA
* Corresponding author. Tel.: +49 551 39 9481 or 8921; fax: +49 551 39 8941 or 14370. Email address: lmaier{at}med.uni-goettingen.de
Received 5 January 2007; accepted 8 January 2007
See reviews in this series by Maier and Bers [5] (pages 631–640), Pitt [6] (pages 641–647), Mattiazzi et al. [7] (pages 648–656), Anderson [8] (pages 657–666), and McKinsey [9] (pages 667–677) in this issue.
Original articles in the series are by Yurukova et al. [10] (pages 678–688) and Vila-Petroff et al. [11] (pages 689–698), also in this issue.
Over the last decade our view of calmodulin and Ca2+/calmodulin kinase (CaMK) in the heart has progressed extensively. This includes improved understanding of the fundamental CaMKII structure, function, and physiological roles [1,2], and more specifically how CaMKII functions in cardiac excitation–contraction coupling [3] and pathophysiological conditions such as hypertrophy and heart failure [4]. Previous reviews on these topics, including the latter in Cardiovascular Research in 2004 that could be said to initiate the present series, have set the backdrop for the broader series of reviews on the burgeoning CaMKII field in the heart in this Review Focus issue.
What drives the current interest in calmodulin and CaMK in the heart? One factor is the potential for calmodulin and CaMK to be intrinsically dependent on changes in intracellular Ca2+ concentration [Ca2+], which regulates not only cardiac contractility but also serves as a ubiquitous second messenger. Indeed, due to the frequent changes in [Ca2+] during systole and diastole, the activity of calmodulin and CaMK can be regulated on a beat-to-beat basis, can exhibit memory (or signal integration), and can participate in both very local and distant signaling within the cell. Thus, during short-term processes such as excitation–contraction coupling where several ion channels, transporters, and pumps work in concert to activate the contractile machinery, CaM–CaMKII may help the myocyte to fine-tune excitability and contractility, This area is reviewed by Maier and Bers [5] and Pitt [6] in this issue. Besides sarcolemmal voltage-gated L-type Ca2+ channels [6], sarcoplasmic reticulum (SR) Ca2+ channels (ryanodine receptors) regulating SR Ca2+ release as well as SR Ca2+ uptake processes are subject to calmodulin and CaMK regulation [5]. Novel data even suggests an important role for CaMKII-dependent regulation and phosphorylation of cardiac Na+ channels [5].
In addition, it is becoming clear that this Ca2+-dependent system may be of particular relevance under various pathophysiological conditions. Mattiazzi et al. [7] nicely summarize what occurs during acidosis, where the intracellular pH drops dramatically (e.g. during ischemic conditions such as myocardial hypoperfusion in severe coronary artery disease). The decreased myocardial contractility seen in this condition may thus be counterbalanced by increased CaMKII-dependent activity leading to improved SR Ca2+ uptake and, hence, at least partial recovery of contractility. Increased CaMKII activity may be a double-edged sword, being beneficial in some cases, but, as clearly reviewed by Anderson [8], CaMKII can also be directly involved in cardiac arrhythmogenic mechanisms. Data presented from both in vitro molecular and single cell experiments as well as in vivo whole-animal models indicate that CaMKII can serve as a pro-arrhythmic signaling molecule and thus represents a previously unexplored anti-arrhythmic target distinct from the classic ion channel proteins.
Interestingly, calmodulin and CaMK may also be important for more chronic cardiac responses. Besides acute changes in excitation–contraction coupling, excitation–transcription coupling may be regulated by CaMK-dependent mechanisms leading to class IIa histone deacetylase (HDAC) phosphorylation in the nucleus and consequent HDAC nuclear export and changes in myocyte enhancer factor-2 (MEF2)-regulated gene expression. In his review, McKinsey [9] suggests that protein kinase D (PKD) and microtubule-associated kinase (MARK) are part of the CaMK superfamily as they have catalytic domains similar to that of CaMKII. As a consequence, PKD and MARK are also able to phosphorylate HDAC in the nucleus, although different HDAC isoforms may be preferred substrates for these enzymes than for CaMKII. Thus CaMKII, along with PKD and MARK, appears to act as HDAC kinases, leading to HDAC derepression and inducing specific hypertrophic responses that contribute to myocardial hypertrophy and remodeling.
Two original articles appearing with this series further highlight the ubiquitous role of CaMKII in pathophysiological conditions of the heart. Yurukova et al. [10] present data on ANP receptor-deficient mice that show cardiac hypertrophy and enhanced contractile performance. The authors convincingly demonstrate that in their mouse model, CaMKII activation and CaMKII-dependent phosphorylation of phospholamban, not protein kinase A (PKA) actions, are the major cause for the improved Ca2+ cycling that results in increased cardiac contractility. In addition, Vila-Petroff et al. [11] in their article show that CaMKII inhibition during ischemia/reperfusion injury in Langendorff-perfused rat hearts protects against myocyte death. One proposed mechanism they suggest is the decrease in SR Ca2+ release or leak due to CaMKII inhibition.
In summary, numerous studies in the recent past have shown that calmodulin and CaMK play important roles in the regulation of cellular excitation–contraction coupling. A significant role for CaMKII in cardiovascular pathophysiology has become increasingly evident, as indicated throughout this series of reviews and original papers. Future research is sure to delineate a plethora of novel mechanisms by which CaMKII and its isoforms are regulated and by which selectivity in phosphorylation of its downstream substrates is achieved, information which in turn holds promise for the discovery of novel therapeutic approaches to treat cardiovascular disease.
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Dr. Maier is funded by the Deutsche Forschungsgemeinschaft (DFG) through an Emmy-Noether-grant (MA 1982/1–5) and a DFG Klinische Forschergruppe grant (MA 1982/2–1). Dr. Brown is funded by NIH grant HL80101. Dr. Bers is funded by the National Institutes of Health (NIH) grants HL64724 and HL80101.
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[Abstract/Free Full Text] - Maier L.S., Bers D.M. Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovasc Res (2007) 73:631–640.
[Abstract/Free Full Text] - Pitt G.S. Calmodulin and CaMKII as molecular switches for cardiac ion channels. Cardiovasc Res (2007) 73:641–647.
[Abstract/Free Full Text] - Mattiazzi A., Vittone L., Mundiña-Weilenmann C. Ca2+/calmodulin-dependent protein kinase: a key component in the contractile recovery from acidosis. Cardiovasc Res (2007) 73:648–656.
[Abstract/Free Full Text] - Anderson M.E. Multiple downstream proarrhythmic targets for calmodulin kinase II: moving beyond an ion channel-centric focus. Cardiovasc Res (2007) 73:657–666.
[Abstract/Free Full Text] - McKinsey T.A. Derepression of pathological cardiac genes by members of the CaM kinase superfamily. Cardiovasc Res (2007) 73:667–677.
[Abstract/Free Full Text] - Yurukova S., Kili
A., Leineweber K., Dybkova N., Maier L.S., Brodde O.E., et al. CaMKII-mediated increased lusitropic responses to β-adreno receptor stimulation in ANP-receptor deficient mice. Cardiovasc Res (2007) 73:678–688.[Abstract/Free Full Text] - Vila-Petroff M., Salas M., Said M., Valverde C., Sapia L., Portiansky E., et al. CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia–reperfusion injury. Cardiovasc Res (2007) 73:689–698.
[Abstract/Free Full Text]
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