Regulation of heterotrimeric G proteins by non-receptor activators

非受体激活剂对异源三聚体 G 蛋白的调节

• 批准号: 8534176
• 负责人: Gregory Gordon Tall
• 金额: $ 30.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534176
• 关键词: Ablation; Adenylate Cyclase; Affinity Chromatography; Attenuated; Binding; Binding Proteins; Biochemical; Biology; Caenorhabditis elegans; Catalysis; Catalytic Domain; Cell Line; Cell division; Cell membrane; Cell surface; Cells; Complement; Cytosol; Defect; Development; Drosophila genus; ES Cell Line; Engineering; Enzymes; Esthesia; Event; Fractionation; Future; G alpha q Protein; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate; Harvest; Heterotrimeric GTP-Binding Proteins; Histones; Homologous Gene; Hormones; Human; Human G(i) Alpha Proteins; Hydrolysis; In Vitro; Intervention; Knock-out; Knowledge; Malignant Neoplasms; Mammalian Cell; Mammals; Mechanics; Mediating; Membrane; Mitosis; Modeling; Mus; Normal Cell; Output; Pathway interactions; Pharmacologic Substance; Phospholipase; Physiological; Physiology; Process; Property; Protein Subunits; Proteins; RNA Interference; RNA Splicing; Reagent; Regulation; Reporter; Research; Role; Sensory; Signal Transduction; Smell Perception; Specificity; Staging; Stem cells; Techniques; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Tubulin; Variant; Work; adult stem cell; base; blastocyst; catalyst; design; embryonic stem cell; gastrulation; hormone regulation; in vivo; neurotransmission; novel; prospective; protein activation; protein expression; protein transport; prototype; public health relevance; repaired; research study; stem cell division; tissue repair; trafficking

DESCRIPTION (provided by applicant): Heterotrimeric G proteins are eminent signal transducing molecules that facilitate human sensation and hormone-regulation of physiology. Traditional G protein signaling pathways are activated by the action of G protein coupled receptors (GPCRs) present on the surface of cells. Recently, new mechanisms of heterotrimeric G protein regulation have been appreciated. Enzymes that are not GPCRs activate G proteins by non-traditional means and regulate pathways not previously attributed to G protein control. Prototypes of these new G protein activators are the Ric-8 proteins. The mammalian Ric-8A homolog activates G protein alpha subunits by stimulating catalysis of GDP for GTP exchange. Ric-8 proteins likely modulate G protein signaling regulation of asymmetric (adult stem cell) and normal cell division (G protein alpha i), aspects of neurotransmission (G protein alpha q), and olfaction (G protein alpha olf). Perhaps underlying this seeming regulation of divergent G protein signaling pathways is the finding that Drosophila RIC-8 appears to be required for the proper expression and plasma membrane localization of heterotrimeric G proteins. The goal of this proposal is to understand in detail, the unique regulation of G protein physiology by both mammalian Ric-8 homologs (A and B). The aims of the proposal are to: (1) examine the hypothesis that Ric-8B proteins activate G protein alpha s subunits by serving as guanine nucleotide exchange catalysts, (2) test the hypothesis in mammals, that Ric-8 proteins are required globally for G protein localization at the cell plasma membrane. (3) test the hypothesis that the mammalian Ric-8A homolog is responsible for activating G protein alpha i- dependent (asymmetric) cell division (4) define the authentic cellular interactions between the compendium of G protein subunits and Ric-8A or Ric-8B. The technology developed to define these interactions will also be used to uncover novel interactions between Ric-8 proteins and other proteins in addition to G proteins. Ric-8 proteins are new G protein activators. Many pharmaceuticals intervene to alter the process of GPCR-mediated G protein activation. Elucidation of the novel mechanisms by which Ric-8 proteins regulate G proteins may enable the engineering of new classes of therapeutics that intervene at the level of Ric-8 activation of G proteins. Furthermore, contributing basic knowledge towards understanding the mechanism(s) by which Ric-8 and G proteins control normal and defective stem cell division could profit: (1) the therapeutic use of stem cells to repair damaged tissues and (2) treatment of stem cell derived cancers. PUBLIC HEALTH RELEVANCE: Heterotrimeric G protein activation is a primary target of pharmaceutical intervention. Defining the unique mechanisms by which Ric-8 proteins activate G proteins will enable the design of new classes of therapeutics that alter the consequences of G protein activation. This research will also define Ric-8 control of G protein-directed stem cell division and contribute efforts to use stem cells for tissue repair and the eradication of cancers derived from defectively dividing stem cells.

描述（由申请人提供）：异源三聚体G蛋白是促进人类感觉和生理调节的杰出信号转导分子。传统的G蛋白信号传导途径通过存在于细胞表面上的G蛋白偶联受体（GPCR）的作用而被激活。最近，异源三聚体G蛋白调节的新机制已被赞赏。不是GPCR的酶通过非传统方式激活G蛋白，并调节以前不属于G蛋白控制的途径。这些新的G蛋白激活剂的原型是Ric-8蛋白。哺乳动物Ric-8A同源物通过刺激GDP催化GTP交换来激活G蛋白α亚基。Ric-8蛋白可能调节不对称（成体干细胞）和正常细胞分裂（G蛋白α i）、神经传递（G蛋白α q）和嗅觉（G蛋白α olf）方面的G蛋白信号传导调节。也许在这种看似不同的G蛋白信号通路的调节下，发现果蝇RIC-8似乎是异源三聚体G蛋白的正确表达和质膜定位所必需的。该提议的目的是详细了解哺乳动物Ric-8同系物（A和B）对G蛋白生理学的独特调节。该提案的目的是：（1）检验Ric-8B蛋白通过充当鸟嘌呤核苷酸交换催化剂激活G蛋白α s亚基的假设，（2）在哺乳动物中检验Ric-8蛋白是G蛋白在细胞质膜上定位所必需的假设。(3)检验哺乳动物Ric-8A同源物负责激活G蛋白α 1依赖性（不对称）细胞分裂的假设（4），确定G蛋白亚基纲要与Ric-8A或Ric-8B之间的真实细胞相互作用。用于定义这些相互作用的技术也将用于发现Ric-8蛋白与G蛋白以外的其他蛋白质之间的新相互作用。Ric-8蛋白是一种新的G蛋白激活剂。许多药物干预以改变GPCR介导的G蛋白活化的过程。Ric-8蛋白调节G蛋白的新机制的阐明可能使得能够工程化干预G蛋白的Ric-8活化水平的新类别的治疗剂。此外，为理解Ric-8和G蛋白控制正常和有缺陷的干细胞分裂的机制贡献基础知识可以有益于：（1）干细胞修复受损组织的治疗用途和（2）干细胞衍生癌症的治疗。 公共卫生相关性：异三聚体G蛋白活化是药物干预的主要目标。确定Ric-8蛋白激活G蛋白的独特机制将能够设计出改变G蛋白激活结果的新类别治疗剂。这项研究还将定义Ric-8对G蛋白指导的干细胞分裂的控制，并为利用干细胞进行组织修复和根除由缺陷分裂干细胞衍生的癌症做出贡献。