Direct Interaction Between GABA-A and GABA-B Receptors

GABA-A 和 GABA-B 受体之间的直接相互作用

• 批准号: 6699301
• 负责人: Randy A. Hall
• 金额: $ 25.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6699301
• 关键词: Direct; Interaction; Between; GABA; Receptors

DESCRIPTION (provided by applicant): Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain. GABA exerts its physiological actions in the brain via the activation of two distinct types of receptor: GABA-A receptors, which are ligand-gated ion channels, and GABA-B receptors, which are G proteincoupled receptors. GABA-A and GABA-B receptors are known to exhibit forms of cross-talk and mutual regulation for which no mechanism has been defined. This project aims to study the importance of a novel and direct interaction found between the GABA-BR1 receptor and the gamma2 subunit of the GABA-A receptor. This physical association may provide a mechanism to allow for direct cross-talk between GABA-A and GABA-B receptors. The structural determinants and physiological significance of this interaction, however, are completely unknown at the present time. The specific regions of GABA-BR1 and the gamma2 subunit of the GABA-A receptor involved in mediating their interaction will be elucidated using a mutagenesis approach in combination with both co-immunoprecipitation and fusion protein pull-down studies. The effects of GABA-A receptor association on GABA-B receptor pharmacology will be studied in ligand binding assays, and GABA-A receptor modulation of GABA-B receptor signaling and internalization will also be analyzed. Furthermore, GABA-B receptor regulation of GABA-A receptor pharmacology, channel activity and phosphorylation will be examined, with an emphasis on determining the functional importance of the direct interaction between GABA-BR1 and the GABA-A receptor gamma2 subunit. These studies will shed new light on the regulation of cellular responses to GABA and the molecular basis for cross-talk between GABA-A and GABA-B receptors. Such information is critical for a comprehensive understanding of pharmaceuticals acting on GABA receptors. GABA-A receptors are the targets for such commonly prescribed therapeutic drugs as benzodiazepines and barbiturates, while the more recently-identified GABA-B receptors represent excellent potential targets for novel therapeutic drugs aimed at treating disorders such as schizophrenia, epilepsy, anxiety, chronic pain and depression.

描述（由申请人提供）： γ-氨基丁酸（GABA）是哺乳动物大脑中主要的抑制性神经递质。 GABA 通过激活两种不同类型的受体在大脑中发挥其生理作用：GABA-A 受体（配体门控离子通道）和 GABA-B 受体（G 蛋白偶联受体）。已知 GABA-A 和 GABA-B 受体表现出串扰和相互调节的形式，但其机制尚未确定。该项目旨在研究 GABA-BR1 受体和 GABA-A 受体的 gamma2 亚基之间发现的新型直接相互作用的重要性。这种物理关联可能提供一种允许 GABA-A 和 GABA-B 受体之间直接串扰的机制。然而，这种相互作用的结构决定因素和生理意义目前完全未知。将使用诱变方法结合免疫共沉淀和融合蛋白下拉研究来阐明参与介导其相互作用的 GABA-BR1 和 GABA-A 受体的 γ2 亚基的特定区域。将通过配体结合测定研究GABA-A受体结合对GABA-B受体药理学的影响，并且还将分析GABA-A受体对GABA-B受体信号传导和内化的调节。 此外，还将检查 GABA-A 受体药理学、通道活性和磷酸化的 GABA-B 受体调节，重点是确定 GABA-BR1 和 GABA-A 受体 gamma2 亚基之间直接相互作用的功能重要性。这些研究将为细胞对 GABA 反应的调节以及 GABA-A 和 GABA-B 受体之间相互作用的分子基础提供新的线索。这些信息对于全面了解作用于 GABA 受体的药物至关重要。 GABA-A 受体是苯二氮卓类和巴比妥类等常用治疗药物的靶点，而最近发现的 GABA-B 受体代表了旨在治疗精神分裂症、癫痫、焦虑、慢性疼痛和抑郁症等疾病的新型治疗药物的极好的潜在靶点。