Mechanisms of CaMKII Activation in the Heart

Abstract

Calcium/calmodulin (Ca(2+)/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 Ca(2+) 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.

Keywords: CaMKII; O-GlcNAc modification; diabetes; heart failure; oxidative stress.

FIGURE 1

Schematic representation of the CaMKII structure/function relationship in the heart. Under basal conditions, the kinase is autoinhibited due to interaction between the regulatory and catalytic domains. Direct activation occurs when Ca²⁺/CaM binds to CaMKII, while subsequent post-translational modification (PTM) results in autonomous kinase activity. Protein interactions with CaMKII autonomously activate CaMKII in the brain but have not yet been demonstrated in the heart. Note that the size of each region is not to scale and will vary by isoform and splice variant of CaMKII.

FIGURE 2

Alignment of the primary structure of regulatory domains from Mus musculus CaMKII isoforms. Specific residues associated with autonomous activation by post-translational modifications have been labeled.