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: 8502709
• 负责人: Patrick Ross O'Neill
• 金额: $ 5.39万
• 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/8502709
• 关键词: Calcium; Cell membrane; Cell physiology; Cell surface; Cells; Disease; Drug Targeting; 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.

描述（由申请人提供）：比任何其他蛋白质家族更多的靶向 G 蛋白偶联受体 (GPCR) 的治疗药物。 G 蛋白通过与质膜 (PM) 上的 GPCR 相互作用来转导在细胞表面启动的信号。这项研究的长期目标是确定新的 G 蛋白相互作用，可以作为新型治疗药物的靶标。 G 蛋白异源三聚体由 α、β 和 γ 亚基组成。在 PM 激活 G 蛋白后，α 亚基和 β-γ 二聚体都会激活下游信号级联。传统上，两人都被认为在此过程中继续担任总理。最近发现，β-γ 二聚体可以从 PM 上移出并易位到高尔基体和内质网 (ER)，其靶向和速率取决于特定的 γ 亚基类型。这些发现需要更好地了解活细胞中 G 蛋白亚基快速可逆运动背后的机制及其在指定细胞对 GPCR 刺激的反应中的功能。 β-γ 易位的 γ 依赖性动力学提供了一种独特的工具，用于识别控制易位的特定 G 蛋白-受体相互作用及其生理作用。我们将利用这些微分动力学来实现两个特定目标。目标 1：检验以下假设：γ 亚基与受体之间的相互作用是受体刺激的 G-β-γ 易位的主要调节因子。目标 2：检验 G-β-γ 易位至内质网 (ER) 靶向肌醇三磷酸受体并调节钙释放的假设。这些实验将测试基于证据的假设，即在 GPCR 激活后，γ 亚基通过调节 β-γ 二聚体在整个细胞中的运动，从而有助于 G 蛋白信号传导的特异性。实验结果有可能确定 γ 亚基和受体之间的特定相互作用，这些相互作用可以有针对性地改变 G 蛋白信号级联中的初始事件。控制这些早期事件对于治疗大量细胞信号传导相关疾病非常重要。