Molecular mechanism of dimeric G protein-coupled receptor signaling

二聚体G蛋白偶联受体信号传导的分子机制

• 批准号: 10382430
• 负责人: QING R FAN
• 金额: $ 37.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382430
• 关键词: Address; Anxiety; Behavior Disorders; Biological Phenomena; Blood; Bone Diseases; Brain Diseases; Calcium-Sensing Receptors; Cognitive; Coupling; Defect; Development; Disease; Epilepsy; Extracellular Domain; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Homeostasis; Human; Lead; Length; Life; Ligand Binding; Ligands; Mediating; Membrane; Metabolism; Minerals; Molecular; Neuraxis; Proteins; Receptor Activation; Research; Signal Transduction; Stimulus; Structural Models; Structure; System; Therapeutic Agents; Transmembrane Domain; Work; addiction; design; dimer; extracellular; neurotransmission; novel therapeutics; receptor; receptor function; spasticity; synaptic inhibition

Summary Our research seeks to uncover the molecular mechanisms of activation and modulation of two dimeric G protein-coupled receptors (GPCRs), human GABAB receptor and human calcium-sensing (CaS) receptor. The GABAB receptor is ubiquitous in the central nervous system, responsible for mediating slow and prolonged synaptic inhibition. Defects in GABAB receptor have been implicated in brain and behavioral disorders, including spasticity, epilepsy, addiction, and anxiety. CaS receptor maintains a stable Ca2+ level in the blood. Abnormal activities of the CaS receptor are associated with a vareity of Ca2+ homeostatic disorders including potentially life threatening hypercalcemic conditions. Both receptors function as obligatory dimers and contain large extracellular domains that are responsible for orthosteric ligand binding. Fundamental questions remain regarding how an extracellular stimulus propagates a signal across the membrane through such a dimeric GPCR system. Building on our structural models for the extracellular domains of each receptor, we plan to determine full-length structures of these GPCRs, including their transmembrane domains, in multiple functional states. For each receptor, we aim to address three main questions: (1) how the dimeric interactions control receptor activation, (2) what the mode of coupling between each receptor and its cognitive G protein is, and (3) how allosteric modulators and auxiliary proteins regulate receptor function. We will combine structural and functional approaches to understand the molecular basis of ligand-induced activation in each receptor system. Our findings will ultimately lead to the development of novel therapeutics for treating diseases associated with the GABAB and CaS receptors.

概括 我们的研究旨在发现激活和调节的分子机制 二聚体G蛋白偶联受体（GPCR），人GABAB受体和人类钙感应 （CAS）受体。 GABAB受体在中枢神经系统中无处不在，负责 介导缓慢和长时间的突触抑制作用。 GABAB受体中的缺陷已与 大脑和行为障碍，包括痉挛，癫痫，成瘾和焦虑。 CAS受体 在血液中保持稳定的Ca2+水平。 CAS受体的异常活性与 CA2+体内稳态疾病的变化，包括潜在威胁生命的高钙质状况。 两种受体都充当强制性二聚体，并且包含大的细胞外域 负责正常配体结合。关于如何 细胞外刺激通过这样的二聚体GPCR系统在整个膜上传播一个信号。 在我们为每个受体的细胞外域的结构模型的基础上，我们计划确定 这些GPCR的全长结构，包括它们的跨膜结构域，在多个功能中 国家。对于每个受体，我们旨在解决三个主要问题：（1）二聚体相互作用如何 控制受体激活，（2）每个受体及其认知G之间的耦合模式 蛋白质是（3）变构调节剂和辅助蛋白如何调节受体功能。我们将 结合结构和功能方法，以了解配体诱导的分子基础 每个受体系统的激活。我们的发现最终将导致小说的发展 治疗与GABAB和CAS受体相关的疾病的治疗剂。