CaM Kinase Inhibition

Abstract

See related article, pages 1092–1099 Calcium/calmodulin-dependent protein kinases (CaM kinases) encompass a family of serine/threonine kinases (CaMKI-CaMKIV) that are regulated by calcium bound to calmodulin.1,2 Four separate genes encode the CaMKII subunits (α, β, γ, δ), and 6 to 12 subunits homo- or heteromultimerize to form the active enzyme. Each subunit contains an N-terminal catalytic domain which binds ATP and substrate, a regulatory domain which includes an autoinhibitory domain and a Ca/Calmodulin binding domain, and a C-terminal association (multimerization) domain. In the heart, a number of splice variants of CaMKIIδ are expressed, including CaMKIIδ2 (CaMKIIδC) and CaMKIIδ3 (CaMKIIδB) which differ from each other by the presence of a nuclear localization signal between the regulatory domain and the association domain in CaMKIIδ3.3 CaMKII functions as a local calcium sensor in the heart. At baseline, the autoinhibitory domain prevents substrate binding to the enzyme.1,2 In cardiac myocytes, intracellular Ca2+ [Ca2+]i rises because of transmembrane influx through L-type Ca2+ channels ( I Ca) or the Na/Ca exchanger and release from internal stores such as the sarcoplasmic reticulum (SR). When intracellular Ca2+ rises, it binds to the EF-hand motifs at the N- and C-terminals calmodulin, an ≈150 amino acid ubiquitous intracellular protein. The Ca/CaM complex then binds to the regulatory domain of CaMKII and removes …