Multiple downstream proarrhythmic targets for calmodulin kinase II: moving beyond an ion channel-centric focus.
The multifunctional Ca(2+) calmodulin-dependent protein kinase II (CaMKII) has emerged as a pro-arrhythmic signaling molecule. CaMKII can participate in arrhythmia signaling by effects on ion channel proteins, intracellular Ca(2+) uptake and release, regulation of cell death, and by activation of hypertrophic signaling pathways. The pleuripotent nature of CaMKII is reminiscent of another serine-threonine kinase, protein kinase A (PKA), which shares many of the same protein targets and is the downstream kinase most associated with beta-adrenergic receptor stimulation. The ability of CaMKII to localize and coordinate activity of multiple protein targets linked to Ca(2+) signaling set CaMKII apart from other "traditional" arrhythmia drug targets, such as ion channel proteins. This review will discuss some of the biology of CaMKII and focus on work that has been done on molecular, cellular, and whole animal models that together build a case for CaMKII as a pro-arrhythmic signal and as a potential therapeutic target for arrhythmias and structural heart disease.
Anderson
Mark E
ME
University of Iowa, Carver College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, E315-A1 GH, Iowa City, IA 52242 USA. mark-e-anderson@uiowa.edu
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology*; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D009206:Myocardium / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology*; D020257:Ventricular Remodeling
D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases