BIOLOGICAL ROLES OF ADENYLYL CYCLASE MODULATION

药理药物如何保持其特异性，仅诱导其 自身特有的细胞反应，尽管激活了许多 重叠的信号通路是我实验室的主要关注点。我们 将研究不同亚型的生理意义 腺酰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 细胞对环境做出反应。这反过来将揭示分子 许多药理制剂的作用机制，并使更多的 特定的药物。 腺酰环化酶是cAMP信号通路的效应分子，是 由一系列具有不同调控功能的异构体组成 机械装置。环化酶调节的某些模式依赖于来自 其他第二信使系统，如钙(Ca~(2+))、钙调蛋白(CaM) 和蛋白激酶。这种监管属性的多样性使 将各种信号整合到协调的营地反应中，并 后续的生理效应取决于特定的 表达了腺酰环化酶的异构体。例如，当前的型号 描述经典条件反射的分子基础被认为 依赖于特定的腺苷酸异构体的协同激活 Ca~(2+)/CaM和G蛋白激活的细胞周期酶。这是唯一已知的生理学 单个环化酶的特定调节机制的作用 亚型，并首次由Rutabaga的遗传研究提出 果蝇的腺酰环化酶。以类似的方式， 每个环化酶同功体的特定生理作用，以及 其功能意义不同的监管模式，可以 由分子、生化和遗传特征决定的 果蝇腺酰环化酶。 这项研究计划的目的是：1)从分子和基因上 腺酰环化酶同工酶亚型的鉴定和生化特征 果蝇，II)确定它们与已知哺乳动物的亲缘关系 腺酰环化酶，以及iii)分离缺乏每个环化酶的苍蝇。这个 这些环化酶中突变体的表型效应应该与 Rutabaga突变体果蝇，提供了对它们的作用的洞察 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.