The adenosine A 2A receptor (A 2A R) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein ␣ olf subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the ␤␥ dimer also performs an active role in this signal transduction process. In principal, sixty distinct ␤␥ dimers could arise from combinatorial association of the five known ␤ and 12 ␥ subunit genes. However, key questions regarding which ␤␥ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein ␥ 7 subtype. Revealing a potentially new signaling paradigm, we show that the level of the ␥ 7 protein controls the hierarchial assembly of a specific G-protein ␣ olf ␤ 2 ␥ 7 heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A 2A R activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein ␥ 7 subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A 2A R G-protein ␣ olf ␤ 2 ␥ 7 interface as a possible therapeutic target for Parkinson disease.G-protein-coupled receptors represent the single largest family of target proteins for drug development. Their actions require the participation of heterotrimeric guanine nucleotide binding proteins (G-proteins) whose roles in these diverse signaling pathways may be determined by their specific ␣␤␥ subunit combinations. The existence of 16 ␣, 5 ␤, and 12 ␥ subtypes creates the potential to generate a large number of distinct G-protein ␣␤␥ heterotrimers (1, 2). Although their biochemical properties have been well studied (3, 4), key questions regarding which G-protein ␣␤␥ heterotrimers actually exist in vivo and determining whether they perform specific signaling roles and biological functions remain to be answered. To address these questions, a gene-targeting approach has been used to delete the various ␣ subunit genes in mice, leading to the identification of physiological functions for most of them (5). By contrast, little attention has focused on the ␤ and ␥ subunit genes. In particular, several features of the ␥ subunit genes suggest they may perform heterogeneous functions in vivo. Analogous to their ␣ partners, the various ␥ subtypes show substantial structural diversity and exhibit pleiotropic patterns of expression (2). Accordingly, we have undertaken a gene targeting approach to systematically ablate the individual ␥ subtypes in mice (6, 7), with the ultimate goal of elucidating their biological functions.Our recent work has demonstrated that knock-out of Gng7, encoding the ␥ 7 subtype, produces a behavioral phenotype result...