Mechanism and role of G-protein subunit translocation in cell signaling

G蛋白亚基易位在细胞信号传导中的机制和作用

• 批准号: 8203869
• 负责人: Patrick Ross O'Neill
• 金额: $ 4.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203869
• 关键词: Calcium; Cell membrane; Cell physiology; Cell surface; Cells; Disease; Drug Delivery Systems; Endoplasmic Reticulum; Event; G Beta Gamma; G-Protein-Coupled Receptors; G-substrate; GTP Binding; GTP-Binding Proteins; Golgi Apparatus; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Inositol; Kinetics; Life; Ligand Binding; Mediating; Membrane; Modeling; Molecular; Movement; Pharmaceutical Preparations; Physiological; Process; Property; Protein Family; Protein Subunits; Protein translocation; Proteins; Receptor Activation; Research; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; Testing; Therapeutic; Therapeutic Agents; design; dimer; evidence base; human disease; new therapeutic target; novel; protein activation; receptor; research study; response; spatiotemporal; therapeutic target; tool

DESCRIPTION (provided by applicant): More therapeutic drugs target G-protein-coupled receptors (GPCRs) than any other family of proteins. G proteins transduce signals initiated at the cell surface through interactions with GPCRs at the plasma membrane (PM). The long term objective of this research is to identify new G protein interactions that can serve as targets for novel therapeutic agents. G protein heterotrimers consist of alpha, beta, and gamma subunits. Upon G protein activation at the PM, the alpha subunit and beta-gamma dimer both activate downstream signaling cascades. Traditionally, both were thought to remain on the PM during this process. Recently, it was discovered that beta-gamma dimers can move off the PM and translocate to the Golgi and endoplasmic reticulum (ER), with targeting and rates that depend on the specific gamma subunit type. These findings call for a better understanding of the mechanisms behind the rapid and reversible movement of G protein subunits in live cells and its function in specifying a cell's response to stimulation of a GPCR. The gamma-dependent kinetics of beta-gamma translocation presents a unique tool for identifying specific G protein-receptor interactions that control translocation, as well as its physiological role. We will exploit these differential kinetics towards two specific aims. Aim 1: Test the hypothesis that interaction between the gamma subunit and the receptor is the primary regulator of receptor-stimulated G-beta-gamma translocation. Aim 2: Test the hypothesis that G-beta-gamma translocation to the endoplasmic reticulum (ER) targets inositol trisphosphate receptors and regulates calcium release. These experiments will test the evidence-based hypothesis that gamma subunits contribute to the specificity of G protein signaling by regulating movement of beta-gamma dimers throughout cell following activation of a GPCR. The findings from the experiments have the potential to identify specific interactions between gamma subunits and receptors that can be targeted to alter the initial events in G protein signaling cascades. Controlling these early events will be important in the treatment of a large number of cell signaling related diseases. PUBLIC HEALTH RELEVANCE: G proteins regulate most of the cell signaling pathways targeted in the treatment of human disease. This research will identify new interactions in G protein signaling that will be important targets for novel therapeutics.

描述（由申请人提供）：比其他任何蛋白质家族都多的治疗药物靶向G蛋白偶联受体（GPCR）。 G蛋白通过与质膜上的GPCR相互作用（PM）在细胞表面启动的传播信号。这项研究的长期目标是确定可以作为新型治疗剂的靶标的新的G蛋白相互作用。 G蛋白异三聚体由Alpha，beta和Gamma亚基组成。 G蛋白在PM处激活后，α亚基和β-γ二聚体都激活了下游信号级联。传统上，在此过程中，两者都被认为保留在PM上。最近，发现β-gamma二聚体可以从PM移动并转移到高尔基体和内质网（ER），其靶向和速率取决于特定的Gamma亚基类型。这些发现要求更好地理解活细胞中G蛋白亚基快速和可逆运动背后的机制及其在指定细胞对GPCR刺激的反应方面的功能。 β-gamma易位的γ依赖性动力学提出了一种独特的工具，用于识别控制转运及其生理作用的特定G蛋白受体相互作用。我们将把这些差异动力学用于两个具体目标。目标1：检验伽马亚基与受体之间相互作用的假设是受体刺激的G-Beta-Gamma易位的主要调节剂。 AIM 2：检验G-Beta-Gamma转移到内质网（ER）靶标肌醇三磷酸受体并调节钙释放的假设。这些实验将检验基于证据的假设，即伽马亚基通过调节GPCR激活后整个细胞中的β-γ二聚体的运动来促进G蛋白信号的特异性。实验的发现具有识别伽马亚基和受体之间的特定相互作用，这些相互作用可针对改变G蛋白信号传导级联中的初始事件。控制这些早期事件对于治疗大量细胞信号相关疾病将很重要。 公共卫生相关性：G蛋白调节针对人类疾病治疗的大多数细胞信号通路。这项研究将确定G蛋白信号传导中的新相互作用，这将是新型治疗剂的重要靶标。