(from abstract) Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in synaptic plasticity in both vertebrates and invertebrates and has properties which suggest that it may be a """"""""molecular switch"""""""". The applicants will analyze the biochemistry of CaMKII in Drosophila and identify components of its biochemical pathways. 1) Analysis of the biochemical function of isoform diversity of the Drosophila CaMKII. This kinase consists of multiple subunits generated by alternative splicing. What are the biochemical consequences of isoform diversity? They will investigate the effects of variable region diversity on regulatory properties of the enzyme. 2) Analysis of the in vivo function of Drosophila CaMKII isoform diversity. Alternative splicing induces changes in the ability of CaM to regulate kinase activity and also regulates substrate specificity in vitro. What is the in vivo function of isoform diversity? They will examine the subcellular localization of the different isoforms and the ability of individual isoforms to phosphorylate unique sets of substrates in intact cells. 3) Regulation of CAMKII levels. They have identified a heterozygous mutation that, in combination with a CaMKII/+ genotype, leads to lethality. Mutations in this gene reduce the level of CaMKII mRNA and protein. They will investigate how this protein regulates CaMKII levels and splicing in the nervous system. 4) Regulation of Ether a go go (Eag) function by CaMKII. The Eag potassium channel has been shown to interact with CaMKII to regulate plasticity. How does CaMKII regulate Eag function? They will investigate the ability of CaMKII to modulate Eag complex formation and channel function. 5) Characterization of novel genes that interact with CaMKII. They will expand the number of identified targets and regulators of CaMKII using both enhancer and suppressor screens for additional interacting genes. Cognitive functions are impaired in many disease states. Understanding the biochemical basis of normal changes in neuronal properties is an important first step in understanding how pathological processes can disrupt brain function. CaMKII has been proposed to play a role in many plastic processes, from long-term potentiation to whole animal behavior. The ability to genetically manipulate CaMKII in Drosophila will allow us to understand not only its biochemical role, but its role in cellular and behavioral processes.
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