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Review
02 April 2014

Calcium/calmodulin (Ca2+/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology. Due to the particularly elegant relationship between the structure and function of the kinase, CaMKII is able to translate a diverse set of signaling events into downstream physiological effects. While CaMKII is typically autoinhibited at basal conditions, prolonged rapid Ca2+ cycling can activate the kinase and allow post-translational modifications that depend critically on the biochemical environment of the heart. These modifications result in sustained, autonomous CaMKII activation and have been associated with pathological cardiac signaling. Indeed, improved understanding of CaMKII activation mechanisms could potentially lead to new clinical therapies for the treatment or prevention of cardiovascular disease. Here we review the known mechanisms of CaMKII activation and discuss some of the pathological signaling pathways in which they play a role.

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117 citations
Review
20 February 2014
Chemical structures of CaMKII inhibitors. (A) The ATP non-competitive inhibitors and controls are: KN-93 (Sumi et al., 1991); KN-92 (Tombes et al., 1995); KN-62 and KN-04 (Ishikawa et al., 1990) HMN-709 (Yokokura et al., 1996). (B) Computational docking of Compound 15b (Mavunkel et al., 2008) illustrates interaction of an ATP competitive inhibitor viewed from the solvent front and shown docked at the kinase “hinge” and interaction at the hydrophobic pocket. The structure of Compound 15b is shown, with the same orientation, with residues that interact at the hinge in blue based on either a crystal structures (Bosutinib) or based on modeling when a reasonable docked structure could be obtained. The compounds above are: Scios-15b (Mavunkel et al., 2008); Bosutinib (Chao et al., 2011); Sanofi-32 (Beauverger et al., 2012); Dainippon A: 8p (Asano et al., 2010); Dainippon B: 25 (Komiya et al., 2012); Rimacalib/SMP-114 (Westra et al., 2010).
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210 citations
Review
11 February 2014
CaMKIIdelta subtypes: localization and function
Charles B. B. Gray
 and 
Joan Heller Brown
Localization and function of CaMKIIδ subtypes in the adult cardiomyocyte. The circles labeled δC and δB represent CaMKIIδ multimers that are composed primarily of δC and δB subunits, respectively. Documented phosphorylation events are indicated by dashed lines. CaMKIIδC regulates Ca2+ homeostasis and currents involved in arrhythmogenesis through phosphorylation of Ca2+ handling proteins and channels. CaMKIIδC can also affect gene transcription through direct and indirect mechanisms including phosphorylation of NFAT and HDAC (sequestering them in the cytosol), increases in p53, and increased nuclear import of NF-κB. The CaMKIIδB subtype has little effect on phosphorylation of Ca2+ handling proteins but increases gene expression through HDAC phosphorylation and nuclear export and activation of HSF1 and GATA4. A putative mechanism for δBredistribution is depicted, showing δBexiting or being excluded from the nucleus due to phosphorylation at a site (Ser332) adjacent to its NLS.

In this review we discuss the localization and function of the known subtypes of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and their role in cardiac physiology and pathophysiology. The CaMKII holoenzyme is comprised of multiple subunits that are encoded by four different genes called CaMKIIα, β, γ, and δ. While these four genes have a high degree of sequence homology, they are expressed in different tissues. CaMKIIα and β are expressed in neuronal tissue while γ and δ are present throughout the body, including in the heart. Both CaMKIIγ and δ are alternatively spliced in the heart to generate multiple subtypes. CaMKIIδ is the predominant cardiac isoform and is alternatively spliced in the heart to generate the CaMKIIδB subtype or the slightly less abundant δC subtype. The CaMKIIδB mRNA sequence contains a 33bp insert not present in δC that codes for an 11-amino acid nuclear localization sequence. This review focuses on the localization and function of the CaMKIIδ subtypes δB and δC and the role of these subtypes in arrhythmias, contractile dysfunction, gene transcription, and the regulation of Ca2+ handling.

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74 citations
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Frontiers in Physiology

The Sodium Pump and Cardiotonic Steroids in Health and Disease
Edited by Alexei Bagrov, Olga Fedorova, Paulo Michel Pinheiro Ferreira
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