RGULATION OF CYCLIC GMP PHOSPHODIESTERASE BY GZ

在我们对细胞如何传递的理解上已经取得了很大进展 外部信号通过特定的细胞表面受体传递给内部 目标。受体结合启动细胞内信号通路， 通常通过异源三聚体G蛋白的激活，最终 导致特定的细胞反应。GZ就是这样一种杂三聚体 表现出独特的生化特征和有限组织的G蛋白 分发。尽管Gz的最初特征提供了 洞察蛋白质的生化特征， Gz的下游目标(S)仍未确定。初步研究 利用酵母双杂交系统表明Gzpha可能 与环状GMP磷酸二酯酶的伽马亚基相互作用。G- 外界尚未对磷酸二酯酶的蛋白质调控进行描述 感觉组织，但最近发现Gz和 大脑不同区域的磷酸二酯酶伽马支持 认为这可能会发生。我们假设磷酸二酯酶伽马是 Gz的天然效应器。包括体外研究和完整的研究 细胞将被用来确定磷酸二酯酶-γ和 GzAlpha关联以及这种相互作用是否可以调制循环 通过激活磷酸二酯酶复合体的核苷酸水平。这个 拟议的研究很可能会导致第一个 表征Gzpha与特定效应器的相互作用 分子，即磷酸二酯酶-伽马。

Much progress has been made in our understanding of how cells transmit external signals via specific cell surface receptors to internal targets. Receptor binding initiates intracellular signaling pathways, often through the activation of heterotrimeric G-proteins, eventually leading to a specific cellular response. Gz is one such heterotrimeric G-protein that exhibits unique biochemical features and limited tissue distribution. Although initial characterization of Gz has provided insight into the biochemical characterization of the protein, the downstream target(s) of Gz remain undefined. Preliminary studies utilizing the yeast two-hybrid system suggest that Gzalpha may possibly interact with the gamma subunit of cyclic GMP phosphodiesterase. G- protein regulation of phosphodiesterases has not been described outside sensory tissues, but recent identification of both Gz and phosphodiesterase gamma in various regions of the brain supports the view that this may occur. We postulate that phosphodiesterase gamma is a natural effector for Gz. Both in vitro studies and studies in intact cells will be conducted to determine whether phosphodiesterase gamma and Gzalpha associate and whether this interaction can modulate cyclic nucleotide levels by activating the phosphodiesterase complex. The proposed studies will quite possibly result in the first characterization the interaction of Gzalpha with a specific effector molecule, namely phosphodiesterase gamma.