Calcium/calmodulin-dependent protein kinase II (CaM kinase) has been implicated in synaptic plasticity in both vertebrates and invertebrates. This enzyme has properties which suggest that it may be a """"""""molecular switch"""""""". Studies in Drosophila melanogaster have shown that CaM kinase is required for learning and memory in an associative behavior, courtship conditioning. The objectives of the proposed study are threefold: 1) Analysis of the biochemistry localization and in vivo function of the Drosophila calcium/calmodulin-dependent protein kinase II isoforms. This kinase, like its mammalian counterparts, has been shown to consist of multiple subunits that show sequence variation between the CaM-binding and association domains. Variations in CaM kinase activity of the isoforms may have functional consequences in the nervous system. The effects of the variable region on regulation of CaM-binding and substrate specificity will be investigated. To determine if differential localization plays a role in the function of the kinase, subcellular distribution of the isoforms will be studied. Finally, we will determine if individual isoforms can rescue viability and behavior on a CaM kinase null background. Understanding the regulation and function of this kinase will allow fuller understanding of its role in neuronal function. 2) Identification of proteins that interact with CaM kinase. We intend to identify and characterize substrates, regulators and localizers of CaM kinase that are involved in neuronal function. One such substrate, Eag, a potassium channel subunit, will be studied with respect to its in vivo phosphorylation. Additional substrates and proteins which interact with CaM kinase to localize and/or regulate it will be identified using the yeast two-hybrid system. Identification of such proteins will allow us to begin to assemble biochemical pathways of synaptic plasticity. 3) Identification of genes that interact with CaM kinase. Mutations at the CaMK locus are lethal in the homozygous state, but viable as CaMK/+ heterozygotes. We will perform an enhancer screen to identify genes which, when mutant, enhance lethality of CaMK/+ heterozygotes. The genes obtained in this screen will provide insight into the functions of CaM kinase and allow us genetic access to biochemical pathways that may be involved in synaptic plasticity. Cognitive functions such as learning and memory 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. CaM kinase has been proposed to play a role in many plastic processes, from long-term potentiation to whole animal behavior. The ability to genetically manipulate CaM kinase in Drosophila will allow us to understand not only its biochemical role, but its role in cellular and behavioral processes.
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