CaMKII: new tricks for an old dog

Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a pivotal signaling molecule in both the brain and the heart. In this issue of Cell, Erickson et al. (2008) demonstrate a mechanism for CaMKII activation by reactive oxygen species that provides a direct link between kinase activation and cardiac dysfunction.

Figure 1. Modifying the δCaMKII Regulatory Domain

The CaMKII regulatory domain is defined as amino acids 282–311 (numbering for δCaMKII; see Hudmon and Schulman, 2002 for review), with an overlapping autoinhibitory domain (green) and a CaM-binding domain (blue). Binding of Ca²⁺/CaM activates CaMKII by disrupting interactions between the autoinhibitory domain and the catalytic substrate-binding site and ATP-binding site. Activation of CaMKII results in autophosphorylation of threonine 287 (T287), which keeps the enzyme active even if Ca²⁺/CaM dissociates. Phosphorylation within the CaM-binding domain at T306 or T307 can occur when CaM dissociates from CaMKII phosphorylated on T287 (Patton et al., 1990) or when unphosphorylated CaMKII is in a complex with CASK (at low Ca²⁺ concentrations), a MAGUK scaffolding protein (Lu et al., 2003). This phosphorylation blocks subsequent Ca²⁺/CaM binding and activation of CaMKII. Erickson et al. (2008) show that M281/M282 can also be modified by oxidation to generate Ca²⁺/CaM-independent activity, suggesting that our definition of the regulatory domain of CaMKII should be expanded to include these residues.