RECEPTOR INTERACTION WITH GTP-REGULATORY PROTEINS

称为G蛋白的GTP结合蛋白家族提供了一种信号 许多细胞表面受体的转导偶联机制。的 受体起催化作用，以介导鸟嘌呤核苷酸交换， G蛋白α亚基的GDP/GTP结合位点。这个过程是 被称为激活，并导致结合GDP的位移， GTP然后，G蛋白的GTP结合形式启动细胞反应 通过改变特定酶或离子通道的活性。的作用 G蛋白在特定的疾病和病理状态有牵连 在神经、神经内分泌和心血管的许多相关研究中， 组织中在两种人类疾病中，假性甲状旁腺功能减退症和生长 激素分泌腺瘤，与α变化直接相关 表达或突变已被证实。G蛋白的致病作用 在其他疾病中的突变尚未得到直接证实。目的 该建议的一个重要方面是使用基因表达显性G蛋白突变体， 改变效应酶调节的转移技术，包括 腺苷酸环化酶和磷脂酶C和A2。的后果 G蛋白调节效应物的组成性刺激或抑制 酶系统将根据代谢的变化来定义， 成纤维细胞、肝癌中特异基因的转录和有丝分裂 和甲状腺细胞。这些研究将描述细胞功能的变化 这是由G蛋白对特定效应酶调节改变引起的 系统.为了解决改变调节的致病作用， 疾病中的腺苷酸环化酶和磷脂酶，显性G蛋白突变体 将在转基因小鼠的肝脏中表达。肝脏变化 功能将被确定并用作定义病理的模型， 从改变细胞功能的生化调节中发展而来， G蛋白突变体在小鼠选定组织中的表达。的 我们工作的长期目标是提供一个分子理解， 哺乳动物组织中调节系统的激素控制以及 当失去这种控制时会出现的病症。这一领域的进展 将有助于开发特定疾病的动物模型， G蛋白调节途径。

The family of GTP-binding proteins, called G proteins, provides a signal transduction coupling mechanism for many cell surface receptors. The receptors act catalytically to mediate guanine nucleotide exchange at the GDP/GTP binding site of the G protein alpha subunit. This process is referred to as activation and results in the displacement of bound GDP for GTP. The GTP-bound form of the G protein then initiates a cellular response by altering the activity of specific enzymes or ion channels. The role of G proteins in specific diseases and pathological states has been implicated in many correlative studies in nervous, neuroendocrine and cardiovascular tissues. In two human diseases, pseudohypoparathyroidism and growth hormonesecreting adenomas, a direct correlation with a change in alphas expression or mutation has been demonstrated. Causative roles of G protein mutations in other diseases have not been directly demonstrated. The aim of this proposal is to express dominant G protein mutants using gene transfer techniques to alter the regulation of effector enzymes including adenylyl cyclase and phospholipases C and A2. The consequence of constitutive stimulation or inhibition of G protein regulated effector enzyme systems will be defined in relation to changes in metabolism, transcription of specific genes and mitogenesis in fibroblasts, hepatomas and thyroid cells. These studies will characterize changes in cell function that result from altered G protein regulation of specific effector enzyme systems. In order to address the causitive role of altered regulation of adenylyl cyclase and phospholipases in disease, dominant G protein mutants will be expressed in the liver of transgenic mice. Changes in liver function will be determined and used as a model to define pathologies that develop from altered biochemical regulation of cell function resulting from the expression of G protein mutants in a selected tissue of the mouse. The long-term objective of our work is to provide a molecular understanding of the hormonal control of regulatory systems in mammalian tissues and the pathologies that develop when this control is lost. Progress in this area will help in developing animal models for specific diseases that involve G protein regulated pathways.