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

摘要 抑制性神经递质GABA通过以下途径在大脑中产生缓慢而持久的抑制 代谢性GABAB受体的激活。GABAB信号的缺陷被认为与 各种神经和情绪障碍，包括痉挛、癫痫、成瘾和焦虑。GABAB 受体是C类G蛋白偶联受体(GPCR)家族的成员，通常 具有二聚体的功能，并具有较大的胞外结构域。根本问题依然存在 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亚基的异源二聚体，受 钾通道四聚含结构域(KCTD)蛋白辅助亚基。我们是 全长GABAB受体及其辅助亚单位及其复合体结构模型的建立 用G蛋白。基于我们的结构分析，我们将确定分子间的关联 GABAB受体和KCTD，描述了多发性骨髓瘤中全长GABAB受体的构象 功能状态，并表征GABAB受体与G之间的变构相互作用 蛋白质。总之，这些研究将促进我们对GABA作用的分子基础的理解 在大脑中，导致了治疗神经疾病的新疗法的发展。

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.