BIOLOGICAL ROLES OF ADENYLYL CYCLASE MODULATION

药理学试剂如何保持特异性， 尽管激活了许多细胞， 重叠的信号通路是我实验室的主要研究方向。我们 将研究不同亚型的生理意义 腺苷酸环化酶及其个体的功能作用 监管互动，以便更好地了解如何 细胞对环境作出反应。这反过来将揭示分子 许多药理学试剂的机制，并使更多的设计 具体药物。 腺苷酸环化酶是cAMP信号通路的效应分子， 由具有不同调节活性的同种型家族组成， 机制等某些环化酶调节模式依赖于来自 其他第二信使系统，如钙（Ca 2+），钙调蛋白（CaM） 和蛋白激酶。这种多样性的监管性质，使 将各种信号整合到协调的cAMP应答中， 随后的生理效应取决于特定的 腺苷酸环化酶亚型表达。例如，当前的模型 描述经典条件作用的分子基础被认为 依赖于腺苷酰的特定同种型的协同活化 Ca ~（2+）/CaM和G蛋白。这是唯一已知的 单个环化酶的特定调节机制的作用 同种型，并首次提出了遗传研究的芜菁 腺苷酸环化酶。同样， 每种环化酶同工型的特定生理作用，以及 其不同的调控模式的功能意义，可以 通过分子、生物化学和遗传特征确定 果蝇腺苷酸环化酶。 这项研究计划的目的是i）分子和遗传学上 鉴定腺苷酸环化酶同工型并进行生化表征， 果蝇，ii）确定它们与已知哺乳动物的亲缘关系 腺苷酸环化酶，和iii）分离每种环化酶缺陷的果蝇。的 这些环化酶突变体的表型效应应该与 芜菁甘蓝突变果蝇，提供深入了解他们的作用， 哺乳动物的对应物。

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.