Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum*
Identifieur interne : 001A70 ( Main/Exploration ); précédent : 001A69; suivant : 001A71Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum*
Auteurs : William F. Schwindinger ; Lauren J. Murphree Mihalcik ; Kathryn E. Giger ; Kelly S. Betz ; Anna Maria Stauffer ; Joel Linden ; Denis Herve [France] ; Janet D. RobishawSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2010.
Abstract
The adenosine A2A receptor (A2AR) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein αolf 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 γ7 subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ7 protein controls the hierarchial assembly of a specific G-protein αolfβ2γ7 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 A2AR activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein γ7 subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A2AR G-protein αolfβ2γ7 interface as a possible therapeutic target for Parkinson disease.
Url:
DOI: 10.1074/jbc.M110.142620
PubMed: 20639202
PubMed Central: 2943273
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>The adenosine A<sub>2A</sub>
receptor (A<sub>2A</sub>
R) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein α<sub>olf</sub>
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<sub>7</sub>
subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ<sub>7</sub>
protein controls the hierarchial assembly of a specific G-protein α<sub>olf</sub>
β<sub>2</sub>
γ<sub>7</sub>
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<sub>2A</sub>
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<sub>7</sub>
subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A<sub>2A</sub>
R G-protein α<sub>olf</sub>
β<sub>2</sub>
γ<sub>7</sub>
interface as a possible therapeutic target for Parkinson disease.</p>
</div>
</front>
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<name sortKey="Linden, Joel" sort="Linden, Joel" uniqKey="Linden J" first="Joel" last="Linden">Joel Linden</name>
<name sortKey="Mihalcik, Lauren J Murphree" sort="Mihalcik, Lauren J Murphree" uniqKey="Mihalcik L" first="Lauren J. Murphree" last="Mihalcik">Lauren J. Murphree Mihalcik</name>
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