BIOLOGICAL ROLES OF ADENYLYL CYCLASE MODULATION

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How pharmacological agents maintain the specificity to elicit only their own characteristic cellular response in spite of activating many overlapping signaling pathways is the broad focus of my laboratory. We will investigate the physiological significance of the different isoforms of adenylyl cyclase and the functional roles of their individual regulatory interactions in order to provide a greater understanding of how cells respond to their environment. This in turn will reveal the molecular mechanisms of many pharmacological agents and enable the design of more specific drugs. Adenylyl cyclase, the effector molecule of the cAMP signaling pathway, is comprised of a family of isoforms possessing distinct regulatory mechanisms. Some modes of cyclase regulation depend upon molecules from other second messenger systems such as calcium (Ca2+), calmodulin (CaM) and protein kinases. This diversity of regulatory properties enables integration of various signals into a coordinated cAMP response and subsequent physiological effects which are dependent upon the particular isoform of adenylyl cyclase expressed. For example, current models describing the molecular basis for classical conditioning are thought to depend upon synergistic activation of a specific isoform of adenylyl cyclase by Ca2+/CaM and G protein. This is the only known physiological role for a particular regulatory mechanism of an individual cyclase isoform and was first suggested by genetic studies on the Rutabaga adenylyl cyclase in Drosophila melanogaster. In a similar manner, the specific physiological roles of each cyclase isoform, as well as the functional significance of its different modes of regulation, can be determined by molecular, biochemical and genetic characterization of Drosophila adenylyl cyclases. The aims of this research proposal are to i) molecularly and genetically identify and biochemically characterize the adenylyl cyclase isoforms in Drosophila, ii) determine their relatedness to the known mammalian adenylyl cyclases, and iii) isolate flies deficient for each cyclase. The phenotypic effects of mutants in these cyclases should, as with the rutabaga mutant Drosophila, provide insight into the role of their mammalian counterparts.