See related articles, pages 758–769 The multifunctional Ca2+ and calmodulin dependent protein kinase (CaMK)II is a serine threonine kinase that plays increasingly evident and important roles in regulating ion channels in heart and other excitable tissues. CaMKII activation initially requires an increase in intracellular Ca2+ that leads to binding of calcified calmodulin (Ca2+/CaM) to the CaMKII regulatory domain. This activating Ca2+/CaM signal is amplified within the CaMKII holoenzyme, which is composed of 10 to 12 monomers arranged in a wheel and spoke pattern (Figure, A), by an autophosphorylation process. Autophosphorylation of Thr286/287 (numbering varies by isoform) markedly increases the avidity of Ca2+/CaM binding to CaMKII but also renders CaMKII constitutively active even in the absence of Ca2+/CaM binding.1 Autophosphorylation of Thr286/287 prevents the reassociation of the autoinhibitory region with the CaMKII catalytic domain, leaving the autophosphorylated kinase in the open and active configuration. Reactive oxygen species modify a pair of methionines (281/282) near the autophosphorylation site to convert CaMKII activity from Ca2+/CaM-dependent to Ca2+/CaM-independent by a process that mirrors autophosphorylation (Figure, A).2 In this issue of Circulation Research , El-Haou et al3 have provided exciting new insights into the association of CaMKII with the MAGUK protein SAP97 by showing that a PDZ motif on the C terminus of KV4.3 partners with the SAP97-CaMKII module to enable CaMKII-dependent gating effects on KV4.3 channels. CaMKII-mediated increases in the transient outward current ( I to) require binding of the SAP97-CaMKII module to the KV4.3 C terminus. These findings provide a molecular framework for understanding how excitable tissues tune repolarization to manage …