Mechanism of activation and modulation in human GABA(B) receptor

人 GABA(B) 受体的激活和调节机制

• 批准号: 10388693
• 负责人: QING R FAN
• 金额: $ 1.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388693
• 关键词: Anxiety; Brain; Brain Diseases; Complex; Defect; Development; Epilepsy; Extracellular Domain; Family; G-Protein-Coupled Receptors; GABA-B Receptor; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Human; Length; Mediating; Modeling; Molecular; Molecular Conformation; Mood Disorders; Neurotransmitters; Potassium Channel; Proteins; Receptor Activation; Receptor Signaling; Regulation; Signal Transduction; Structural Models; Structure; Therapeutic Agents; addiction; base; brain behavior; design; dimer; gamma-Aminobutyric Acid; member; nervous system disorder; neurotransmission; novel therapeutics; receptor; spasticity

Summary The inhibitory neurotransmitter GABA produces slow and prolonged inhibition in the brain through activation of metabotropic GABAB receptors. Defects in GABAB signaling have been implicated in various neurological and mood disorders including spasticity, epilepsy, addiction and anxiety. GABAB receptor is a member of the class C G protein-coupled receptor (GPCR) family, which typically functions as a dimer and possesses large extracellular domains. Fundamental questions remain concerning the molecular mechanisms underlying activation and modulation of these class C receptors. The GABAB receptor is a heterodimer of GABAB1 and GABAB2 subunits and is modulated by the potassium channel tetramerization domain-containing (KCTD) protein auxiliary subunits. We are developing structural models for full-length GABAB receptor, its auxiliary subunits and their complexes with G-protein. Based on our structural analysis, we will determine the molecular association between GABAB receptor and KCTD, describe the conformations of full-length GABAB receptor in multiple functional states, and characterize the allosteric interaction between the GABAB receptor and G proteins. Together, these studies will advance our understanding of the molecular basis of GABA action in the brain, leading to the development of novel therapeutics for treating neurological diseases.

概括 抑制性神经递质 GABA 通过以下方式在大脑中产生缓慢而持久的抑制： 代谢型 GABAB 受体的激活。 GABAB 信号传导缺陷与 各种神经和情绪障碍，包括痉挛、癫痫、成瘾和焦虑。氨基丁酸 受体是 C 类 G 蛋白偶联受体 (GPCR) 家族的成员，通常 作为二聚体发挥作用并具有大的细胞外结构域。基本问题仍然存在 关于这些 C 类受体激活和调节的分子机制。 GABAB 受体是 GABAB1 和 GABAB2 亚基的异二聚体，受 含钾通道四聚化结构域 (KCTD) 的蛋白质辅助亚基。我们是 开发全长 GABAB 受体、其辅助亚基及其复合物的结构模型 与G蛋白。根据我们的结构分析，我们将确定之间的分子关联 GABAB 受体和 KCTD，描述了多种形式的全长 GABAB 受体的构象 功能状态，并表征 GABAB 受体和 G 之间的变构相互作用 蛋白质。这些研究将共同​​推进我们对 GABA 作用分子基础的理解 在大脑中，导致治疗神经系统疾病的新疗法的开发。