Sticky fingers: CaMKII finds a home on another ion channel.

The multifunctional Ca 2 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 Ca that leads to binding of calcified calmodulin (Ca /CaM) to the CaMKII regulatory domain. This activating Ca /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 Ca /CaM binding to CaMKII but also renders CaMKII constitutively active even in the absence of Ca /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 Ca /CaM-dependent to Ca /CaMindependent 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 (Ito) require binding of the SAP97CaMKII module to the KV4.3 C terminus. These findings provide a molecular framework for understanding how excitable tissues tune repolarization to manage cellular Ca entry.