INHIBITORY REGULATION OF ADENYLATE CYCLASE

广泛分布的激素受体抑制，而不是 近年来已经注意到刺激腺苷酸环化酶活性。 可利用该抑制途径的调节剂包括阿片类药物， 腺苷、多巴胺、三尖杉酯碱、毒蕈碱胆碱能和 α-肾上腺素能效应器 表达的功能要求 抑制作用不同于刺激作用。 但目前尚不清楚 不同的激素受体和GTP调节蛋白是否 与这种抑制性调节有关。 当前的主要目标 建议是：i）表征α 2-肾上腺素能的相互作用， 和腺苷-Ri受体与GTP调节蛋白（Ni）在促进 分别抑制血小板和脂肪细胞中的腺苷酸环化酶; ii）溶解抑制性受体和GTP调节蛋白;和 iii）将抑制性蛋白质的性质与 已知其刺激腺苷酸环化酶的对应物。 成就 这些目标的实现依赖于针对这些疾病的功能测定的发展。 调节组分，当存在于膜中时，或 增溶作用 GTP水解在抑制调节中的作用将 也要评估。 GTP的水解在刺激细胞凋亡中起着重要作用。 酶;初步结果表明在抑制中的单独作用。 酶活性的动力学研究将在以下相互作用上进行： GTP和不可水解的类似物GPPNHP。 这些研究旨在 扩大我们的见解的结构和动力学性质的双重 调节腺苷酸环化酶系统。 长期的结果是， 研究将提供一个理解，这是目前还没有 一大批激素的基本作用机制 和神经递质。

A widespread distribution of hormone receptors which inhibit rather than stimulate adenylate cyclase activity has been noted in recent years. Modulators which may utilize this inhibitory pathway include opiates, adenosine, dopamine, prostaglandins, muscarinic cholinergic and alpha-adrenergic effectors. Functional requirements for the expression of inhibition are distinct from those of stimulation. However, it is unclear whether distinct sets of hormone receptors and GTP regulatory proteins are associated with this inhibitory regulation. Primary goals of the present proposal are: i) to characterize the interaction of the alpha2-adrenergic and adenosine-Ri receptors with GTP regulatory proteins (Ni) in promoting inhibition of adenylate cyclase in platelets and adipocytes, respectively; ii) to solubilize inhibitory receptors and GTP regulatory proteins; and iii) to compare the properties of the inhibitory proteins with what is known of their counterparts which stimulate adenylate cyclase. Achievement of these goals is dependent on the development of functional assays for the regulatory components either when present in membranes or following solubilization. The role of GTP hydrolysis in inhibitory regulation will also be assessed. Hydrolysis of GTP plays a central role in stimulation of the enzyme; preliminary results indicate a separate role in inhibition. Kinetic studies of enzyme activity will be performed on the interaction of GTP and the nonhydrolyzable analog, GPPNHP. These studies are intended to expand our insights into the structural and kinetic properties of dually regulated adenylate cyclase systems. The long term outcome of these studies will be to provide an understanding, which is presently not available, of the basic mechanism of action of a large group of hormones and neurotransmitters.