Protein phosphorylation is a central mechanism in vertebrates for the regulation of signaling. With regard to the cardiovascular system, phosphorylation of myocyte targets is critical for the regulation of excitation contraction coupling, metabolism, intracellular
calcium regulation, mitochondrial activity, transcriptional regulation, and cytoskeletal dynamics. In fact, pathways that tune
protein kinase signaling have been a mainstay for cardiovascular
therapies for the past 60 years. The
calcium/calmodulin-dependent protein kinase II (
CaMKII) is a multifunctional
serine/threonine kinase with numerous roles in human physiology. Dysfunction in
CaMKII-based signaling has been linked with a host of cardiovascular phenotypes including
heart failure and
arrhythmia, and
CaMKII levels are elevated in human and
animal disease models of
heart disease. While nearly a decade has been invested in targeting
CaMKII for the treatment of
heart failure and
arrhythmia phenotypes, to date, approaches to target the molecule for antiarrhythmic benefit have been unsuccessful for reasons that are still not entirely clear, although (1) lack of compound specificity and (2) the multitude of downstream targets are likely contributing factors. This review will provide an update on current pathways regulated by
CaMKII with the goal of illustrating potential upstream regulatory mechanisms and downstream targets that may be modulated for the prevention of cardiac electrical defects. While the review will cover multiple aspects of
CaMKII dysfunction in
cardiovascular disease, we have given special attention to the potential of
CaMKII-associated late Na(+) current as a novel therapeutic target for
cardiac arrhythmia.