Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation

Discs large (DLG) mediates the clustering of synaptic molecules. Here we demonstrate that synaptic localization of DLG itself is regulated by CaMKII. We show that DLG and CaMKII colocalize at synapses and exist in the same protein complex. Constitutively activated CaMKII phenocopied structural abnormalities of dig mutant synapses and dramatically increased extra-junctional DLG. Decreased CaMKII activity caused opposite alterations. In vitro, CaMKII phosphorylated a DLG fragment with a stoichiometry close to one. Moreover, expression of site-directed dig mutants that blocked or mimicked phosphorylation had effects similar to those observed upon inhibiting or constitutively activating CaMKII. We propose that CaMKII-dependent DLG phosphorylation regulates the association of DLG with the synaptic complex during development and plasticity, thus providing a link between synaptic activity and structure.