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: 10588166
• 负责人: QING R FAN
• 金额: $ 48.6万
• 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/10588166
• 关键词: Address; Anxiety; Behavior Disorders; Biological Phenomena; Blood; Bone Diseases; Brain Diseases; Calcium-Sensing Receptors; Central Nervous System; Cognitive; Coupling; Defect; Development; Disease; Epilepsy; Extracellular Domain; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Homeostasis; Human; Hypercalcemia; Length; Life; Ligand Binding; Ligands; Mediating; Membrane; Metabolism; Minerals; Molecular; 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.

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