Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus

The multifunctional Ca²⁺ 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 Ca²⁺ 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 β-adrenergic receptor stimulation. The ability of CaMKII to localize and coordinate activity of multiple protein targets linked to Ca²⁺ 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.