Novel Aspects of Golf Signaling



 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.