Beta/Gamma Subunit Heterogeniety in G Proteins

G 蛋白中的 β/γ 亚基异质性

• 批准号: 7913465
• 负责人: JANET D ROBISHAW
• 金额: $ 9.06万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913465
• 关键词: Ablation; Adenylate Cyclase; Alcohols; Anatomy; Behavioral; Biochemical; Brain; Cells; Clinical; Cognitive; Corpus striatum structure; Defect; Disease; Dopamine Receptor; Drug Addiction; Exhibits; Functional disorder; Funding; G-Protein Signaling Pathway; GTP-Binding Proteins; Gene Targeting; Gilles de la Tourette syndrome; Golf; Grant; Huntington Disease; Immune; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Molecular; Motor; Mus; Nature; Neurologic; Neurotransmitters; Organism; Output; Parkinson Disease; Phenocopy; Phenotype; Physiological; Process; Property; Proteins; Receptor Signaling; Reporting; Research Personnel; Role; Schizophrenia; Seizures; Signal Pathway; Signal Transduction; Specificity; Structure; Time; To specify; Translations; Weight; Work; base; cell type; drug discovery; mouse model; novel; programs; response

The specificity of G protein signaling in brain is essential for the translation of neurotransmitter activity into meaningful neurological responses. The challenge is to understand how this is accomplished. From the beginning, this grant has focused on how the specificity of signaling is encoded in the subunit structure of the G protein. Historically, the diverse alpha subunits were assumed to specify the roles of the G proteins in particular signaling pathways. However, our recent work has called this assumption into question with the discovery of similarly diverse gamma subtypes whose unique signaling properties were revealed for the first time through the use of a gene targeting approach. During the next funding period, we propose to focus on the Gng7 mouse model to elucidate how deletion of the gamma 7 subtype disrupts the D1 dopamine receptor signaling in brain, and how this signaling defect produces the distinctive phenotype of these mice. The specific aims of this grant are: 1) to identify the nature and full range of the neurological phenotype; 2) to determine the cellular basis for the phenotype; 3) to elucidate the biochemical defects responsible for various aspects of the phenotype; and 4) to investigate the newly discovered role of the gamma 7 subtype in controlling the assembly of the Golf protein. Because dysfunction of D1 dopamine receptor signaling is associated with numerous diseases, including Parkinson's disease, schizophrenia, Tourette's syndrome, Huntington's disease, and alcohol and drug addiction, the fundamental importance and clinical ramifications of this work are enormous.

大脑中 G 蛋白信号传导的特异性对于将神经递质活动转化为有意义的神经反应至关重要。挑战在于理解这是如何实现的。从一开始，这笔资助就重点关注 G 蛋白亚基结构中信号传导的特异性是如何编码的。历史上，不同的 α 亚基被认为指定了 G 蛋白在特定信号通路中的作用。然而，我们最近的工作对这一假设提出了质疑，因为发现了类似多样化的伽马亚型，其独特的信号传导特性首次通过使用基因靶向方法被揭示。在下一个资助期间，我们建议重点关注 Gng7 小鼠模型，以阐明 γ 7 亚型的缺失如何破坏大脑中的 D1 多巴胺受体信号传导，以及这种信号传导缺陷如何产生这些小鼠的独特表型。该资助的具体目标是：1）确定神经表型的性质和全部范围； 2) 确定表型的细胞基础； 3）阐明导致表型各个方面的生化缺陷； 4) 研究新发现的γ 7 亚型在控制高尔夫蛋白组装中的作用。由于 D1 多巴胺受体信号传导功能障碍与多种疾病相关，包括帕金森病、精神分裂症、抽动秽语综合征、亨廷顿病以及酒精和药物成瘾，因此这项工作的根本重要性和临床影响是巨大的。