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 ??? subunit structures of the G-proteins. Historically, the diverse ? subtypes were assumed to specify their signaling roles. However, our work has challenged this dogma with the discovery of diverse ? subtypes whose unique signaling functions are identified for the first time. Notably, our production of Gng7-/- mice provides irrefutable proof that the ?7 subtype performs a novel role in the striatum by directing the ordered assembly of a specific G-?olf?2?7 heterotrimer that operates downstream of the D1 dopamine and A2a adenosine receptors in striatum. Forming the basis for this proposal, loss of the ?7 protein disrupts the G-?olf?2?7 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-?olf?2?7 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- ?olf?2?7 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-?olf?2?7 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.
This grant revolves around understanding the G-olf signaling pathways that normally control locomotion, motivation, and reward, but when dysfunctional, contribute to Parkinson's, Huntington's, and addictive disorders. Our identification of a striatal-specific G-a? combination acting downstream of the D1 dopamine and A2a adenosine receptors will open the door for more selective treatment of these diseases.
