Dataset Information

Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum.

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 ?(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.

SUBMITTER: Schwindinger WF

PROVIDER: S-EPMC2943273 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum.

Schwindinger William F WF Mihalcik Lauren J Murphree LJ Giger Kathryn E KE Betz Kelly S KS Stauffer Anna Maria AM Linden Joel J Herve Denis D Robishaw Janet D JD

The Journal of biological chemistry 20100716 39

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 question ...[more]

PMID: 20639202

Similar Datasets

Project description:Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.

Dataset Information

Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum.

Publications

Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets