The roles of heterotrimeric GTP-binding proteins in signal transduction

本研究项目是1993年至1995年由10名研究人员组织的，目的是研究α-γ-异源三聚体GTP结合蛋白（G蛋白）在信号转导中的作用。本研究项目的主要研究结果概述如下。1)克隆了与G蛋白偶联的膜结合受体的cDNA。这包括一种新的光受体，视胞素，它可能在褪黑激素合成的昼夜节律中发挥重要作用，以及各种类型的前列腺素受体。2)G蛋白的β-γ亚基刺激G蛋白偶联膜受体（GR）的磷酸化，如通过GR激酶（GRKs）的毒蕈碱乙酰胆碱受体。GRKs的这种受体磷酸化似乎参与了磷酸化受体分子的内化。3)Wortmannin是一种特异性的磷脂酰肌醇（PI）3-激酶抑制剂。使用这种特异性抑制剂，PI 3-激酶被证明参与通过两种不同类型的膜受体介导的信号传导途径，一种具有酪氨酸激酶活性，另一种激活G蛋白。4)磷脂酶D的活性不仅受G蛋白的刺激，也受小的GTP结合蛋白如Rho和ARF的刺激。5）G蛋白的翻译后修饰，α亚基的脂肪酸加成，γ亚基的异戊二烯化和磷酸化，在信号转导蛋白的功能调节中起重要作用。

This research project was organized by ten and a couple of investigators in order to study the roles of alphabetagamma-heterotrimeric GTP-binding proteins (G proteins) in signal transduction from 1993 to 1995. The major findings obtained in this research project are summarized as follows. 1) The cDNAs of membrane-bound receptors that coupled to G proteins were cloned. Such included a novel photo-receptor, pinopsin, which may play an important role in the circadian rhythm of melatonin synthesis, and various types of prostaglandin receptors. 2) The betagamma subunits of G proteins stimulated the phosphorylation of G protein-coupled membrane receptors (GR) such as muscarinic acetylcholine receptors by GR kinases (GRKs). This receptor phosphorylation by GRKs appeared to be involved in the internalization of the phosphorylated receptor molecules. 3) Wortmannin was found to be a specific inhibitor of phosphoinositide (PI) 3-kinase. Using this specific inhibitor, PI 3-kinase was shown to be involved signal transduction pathways mediated through two different types of membrane receptors, one possessing tyrosine kinase activity and the other activating G proteins. 4) Phospholipase D activity was stimulated not only by G proteins but also by small GTP-binding proteins such as Rho and ARF.5) The Post-translational modification of G proteins, fatty-acid addition to alpha subunits, isoprenylation and phosphorylation of gamma subunits, playd important roles in the functional regulation of the signal-transducing proteins.