Cover picture: Regulation of CaMKII by autophosphorylation. Autophosphorylation within the regulatory domain of CaMKII defines several activity states for the kinase. In the absence of Ca²⁺/CaM and autophosphorylation, CaMKII is inactive. Binding of Ca²⁺/CaM activates the kinase for substrate phosphorylation, bringing it to 100% of its maximal activity. Binding of two Ca²⁺/CaMs to adjacent subunits stimulates inter-subunit phosphorylation of Thr²⁸⁶. The off-rate of Ca²⁺/CaM from pThr²⁸⁶ CaMKII is decreased >1000-fold, resulting in an enzyme that remains at 100% of its maximal Ca²⁺/CaM-stimulated activity even as calcium falls in the cell. Once Ca²⁺/CaM dissociates, the enzyme remains active, but at a lower level than with saturating Ca²⁺/CaM, having between 20 and 80% of its maximal Ca2²⁺/CaM-stimulated activity. The dissociation of Ca²⁺/CaM also uncovers additional sites in the regulatory domain (Thr³⁰⁵ and Thr³⁰⁶) that rapidly become autophosphorylated. The pThr²⁸⁶/pThr³⁰⁵/ pThr³⁰⁶ CaMKII remains active at 20-80% of maximal activity because of pThr²⁸⁶ but is incapable of binding Ca²⁺/CaM. Phosphatase activity is required to reset the kinase to its basal state. For details, see the article by Griffith in this issue (pages 8391–8393).