Abstract
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 α(olf) subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the βγ dimer also performs an active role in this signal transduction process. In principal, sixty distinct βγ dimers could arise from combinatorial association of the five known β and 12 γ subunit genes. However, key questions regarding which βγ 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 γ(7) subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ(7) protein controls the hierarchial assembly of a specific G-protein α(olf)β(2)γ(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 γ(7) subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A(2A)R G-protein α(olf)β(2)γ(7) interface as a possible therapeutic target for Parkinson disease.
Highlights
G-protein-coupled receptors represent the single largest family of target proteins for drug development
Our recent work has demonstrated that knock-out of Gng7, encoding the ␥7 subtype, produces a behavioral phenotype resulting in part from a localized defect in dopamine D1 receptor (D1R)2 signaling in the brain [6]
Because blockade of this receptor has been shown to reverse the hypolocomotor phenotype resulting from dopamine deficiency [23] and dysfunctional dopamine signaling [24], the A2A receptor (A2AR) signaling components are increasingly recognized as valid therapeutic targets for treating Parkinson disease and for reducing the side effects of levodopa therapy [25, 26]
Summary
D1R, dopamine D1 receptor; A2AR, adenosine A2A receptor; SP, striatopallidal; SN, striatonigral; GTP␥S, guanosine 5Ј-3-O-(thio)triphosphate. G-protein ␥7 [6] or ␣olf [13] subunits, respectively, we showed that levels of the ␣olf and 2 proteins were selectively and coordinately reduced in Gng7Ϫ/Ϫ mice, whereas levels of ␥7 were largely unaffected in the GnalϪ/Ϫ mice. Loss of the G-protein ␥7 subunit led to defects in both D1R [6] and A2A receptor activation of adenylyl cyclase without producing any gross alterations in locomotor behavior typical of Parkinson disease. These findings contribute to a growing literature that suggests that blockade of A2AR signaling in the striatum may be an effective strategy for treating various neurological and addictive disorders
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