Beta/Gamma Subunit Heterogeniety in G Proteins

大脑中G蛋白信号传导的特异性对于将神经递质活性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，这项资助就专注于如何在G蛋白的亚基结构中编码信号的特异性。从历史上看，不同的α亚基被认为可以指定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，发现了类似的不同γ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出来。在下一个资助期内，我们建议将重点放在Gng 7小鼠模型上，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，以及这种信号缺陷如何产生这些小鼠的独特表型。这项资助的具体目的是：1）确定神经学表型的性质和全部范围; 2）确定表型的细胞基础; 3）阐明负责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许多疾病相关，包括帕金森病、精神分裂症、图雷特综合征、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。

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.