Novel Aspects of Golf Signaling

 描述(由申请者提供)：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在不同大脑区域、电路和细胞类型中工作的更多通路的协调。我们的实验室重点研究了这些信号通路的多样性和特异性是如何在G蛋白的αβγ亚单位结构中编码的。在历史上，不同的α亚型被认为指定了它们的信号角色。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发现。值得注意的是，我们生产的GNG7-/-小鼠提供了无可辩驳的证据，证明γ7亚型 通过指导特定G-αOffβ2γ7的有序组装在纹状体中发挥新的作用 在纹状体的D1多巴胺和A2a腺苷受体下游工作的异三聚体。作为这一提议的基础，γ7蛋白的丢失会扰乱G-αOLFβ2γ7的组装，并产生有缺陷的吗啡反应。由于基因缺失的全球性，目前尚不清楚吗啡反应性的缺陷是否反映了纹状体-黑质神经元中作用于D1R下游的G-αOffβ2γ7异三聚体的需求，或纹状体-苍白球神经元中A2a腺苷受体(A2aR)的需求，或者两者兼而有之。因此，我们将使用我们新创建的条件性Gng7小鼠：1)从基因上剖析G-G-αOffβ2γ7异源三聚体在介导 2)确定细胞基础和受影响的信号通路(S)；3)探索G-α、OLF、β、2、γ、7的异源三聚体组成对这些受体的配体结合特性的影响。这一新知识最终可能导致制定更好的战略，以防止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.