CaMKII plays an important role in learning in Drosophila as well as in other animals. Localization of CaMKII allows this highly abundant enzyme to achieve specificity of action. Scaffolding interactions can also regulate the activity of CaMKII. We have characterized two such interactions: an interaction with the Eag potassium channel that renders the enzyme constitutively active without kinase autophosphorylation and an ATP-dependent interaction with Camguk (Cmg), a MAGUK protein that enhances inactivating autophosphorylation of the kinase.
Our specific aims are: (1) Determine the role of alternative splicing in the subcellular localization of CaMKII. CaMKII localization is aberrant in a mutant that alters CaMKII isoform ratios and CaMKII can enter the nucleus in eag mutants. We will investigate the mechanisms of CaMKII subcellular localization and nuclear translocation. (2) Determine the role of the CaMKIhEag complex. We will define the molecular basis of the interaction and use this information to design specific inhibitors to use in vivo in electrophysiological and behavioral assays. (3) Determine the role of the CaMKIhCmg complex. We will define the molecular basis of the interaction and use inhibitors and overexpression to probe the role of Cmg in the regulation of CaMKII activity. Cmg promotes formation of a calcium-insensitive pool of CaMKII, which may be important in modulating calcium signaling during plasticity. These studies will provide insight into the regulation of a protein that is fundamental to synaptic plasticity. Understanding these pathways will advance our knowledge of the basic processes that shape behavior.
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