Novel Aspects of Golf Signaling

 描述（由申请人提供）：G蛋白信号通路几乎控制着体内的每一个过程。在任何时候，特定神经元的输出反映了几个信号通路的整合，而生物体的神经反应需要协调在不同大脑区域，回路和细胞类型中运行的更多通路。我们的实验室专注于这些信号通路的多样性和特异性如何在G蛋白的αβγ亚基结构中编码。历史上，不同的α亚型被认为指定了它们的信号作用。然而，我们的工作挑战了这一教条，发现了不同的γ亚型，其独特的信号功能首次被确定。值得注意的是，我们生产的Gng 7-/-小鼠提供了无可辩驳的证据，即γ7亚型 通过指导特定的G-αolfβ2γ7的有序组装在纹状体中发挥新的作用 异源三聚体，其在纹状体中的D1多巴胺和A2 a腺苷受体的下游起作用。γ7蛋白的缺失破坏了G-αolfβ2γ7的组装，并产生了有缺陷的吗啡反应性，这构成了这一提议的基础。由于基因缺失的全局性质，尚不清楚缺陷的吗啡反应性是否反映了对G-αolfβ2γ7异源三聚体的需求，该异源三聚体作用于黑质纹状体神经元中的D1多巴胺受体（D1 R）、纹状体苍白球神经元中的A2 a腺苷受体（A2 aR）或两种受体的下游。因此，我们将使用我们新创建的条件性Gng 7小鼠：1）从遗传学上剖析G-G- αolfβ2γ7异源三聚体在介导细胞凋亡中的细胞类型特异性作用。 自发和获得性行为; 2）鉴定细胞基础和受影响的信号传导途径;和3）探索G-αolfβ2γ7异源三聚体组成在多大程度上影响这些受体的配体结合性质。这些新知识最终可能会导致制定更好的策略来预防或改善处方阿片类药物滥用，目前美国政府每年花费3000亿美元。

 DESCRIPTION (provided by applicant): G-protein signaling pathways control virtually every process in the body. At any time, the output of a particular neuron reflects the integration of several signaling pathways, while the neurological response of the organism requires the coordination of many more pathways operating in different brain regions, circuits and cell types. Our laboratory focused on how the diversity and specificity of these signaling pathways are encoded in the αβγ subunit structures of the G-proteins. Historically, the diverse α subtypes were assumed to specify their signaling roles. However, our work has challenged this dogma with the discovery of diverse γ subtypes whose unique signaling functions are identified for the first time. Notably, our production of Gng7-/- mice provides irrefutable proof that the γ7 subtype performs a novel role in the striatum by directing the ordered assembly of a specific G-αolfβ2γ7 heterotrimer that operates downstream of the D1 dopamine and A2a adenosine receptors in striatum. Forming the basis for this proposal, loss of the γ7 protein disrupts the G-αolfβ2γ7 assembly and produces defective morphine responsiveness. Because of the global nature of the gene deletion, it is not clear whether the defective morphine responsiveness reflects a requirement for the G-αolfβ2γ7 heterotrimer acting downstream of the D1 dopamine receptor (D1R) in striato-nigral neurons, the A2a adenosine receptor (A2aR) in striato-pallidal neurons, or both receptors. Accordingly, we will use our newly created conditional Gng7mice: 1) to genetically dissect the cell type specific roles of the G- G- αolfβ2γ7 heterotrimer in mediating spontaneous and acquired behaviors; 2) to identify the cellular basis and the affected signaling pathway(s); and 3) to explore to what extent the G-αolfβ2γ7 heterotrimer composition influences the ligand binding properties of these receptors. This new knowledge may eventually lead to the development of better strategies to prevent or ameliorate prescription opiate abuse that currently costs the US government $300 billion a year.