Ca2????dependent protein kinase II (CaMKII) is critical for normal synaptic plasticity, learning and memory. The long-term goal is to understand mechanisms that allow dendritic CaMKII to appropriately regulate neurotransmitter receptors, translation, excitability, cytoskeletal dynamics and cell morphology. Autophosphorylation of dodecameric CaMKII holoenzymes at multiple sites interprets dynamic dendritic calcium signals, "fine-tuning" the kinase activity. Our overall hypothesis is that CaMKII subcellular localization and signaling is modulated by interactions with CaMKII Associated Proteins (CaMKAPs). In the initial funding cycle, we identified several actual or putative CaMKAPs, including NMDA-type glutamate receptor (NMDAR) NR2B subunits, splice variants of densin-180, a-actinin-2 and SAP97. CaMKII activation/autophosphorylation differentially modulates these interactions, which in turn reciprocally regulate CaMKII activity by distinct mechanisms. In addition, we showed that CaMKII can coordinate complexes involving multiple CaMKAPs, with a-actinin-2 potentially providing a link to the actin cytoskeleton. Most excitingly, binding of CaMKII to NR2B appears to be important in a novel CaMKII-enhanced desensitization of NR2B-containing NMDARs. The continuing application proposes to further test our overall hypothesis using biochemical, molecular, electrophysiological, microscopic and immunological techniques. The roles of NR2B interaction with aactinin-2 and CaMKII in NMDAR regulation and CaMKII targeting will be established in cell culture models and using novel knockout mice that eliminate NMDAR NR2A or NR2B subunits. Studies in cell culture will also establish new roles for densin-180 splice variant complexes with CaMKII and a-actinin-2. Finally, the roles of SAP97 and other CaMKAPs in modulating GluR1 phosphorylation will be determined. Derangements of synaptic transmission contribute to many neurological diseases, including Parkinson's Disease, addiction, depression, schizophrenia and epilepsy, and we have shown that CaMKII is a viable therapeutic target in other biological systems. Consequently, these mechanistic studies will improve our fundamental understanding of the role of CaMKII in regulating synaptic transmission, providing insight into potential new strategies for treatment of multiple brain disorders.