ParkinsonFranceV1, Main, Exploration, bibRecord, 001A70

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 : 001A71

Adenosine 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. Robishaw

Source :

The Journal of Biological Chemistry [ 0021-9258 ] ; 2010.

RBID : PMC:2943273

Abstract

The adenosine A_2A receptor (A_2AR) 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 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 α_olfβ₂γ₇ 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_2AR 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 A_2AR G-protein α_olfβ₂γ₇ interface as a possible therapeutic target for Parkinson disease.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943273

DOI: 10.1074/jbc.M110.142620
PubMed: 20639202
PubMed Central: 2943273

Affiliations:

Le document en format XML

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 Receptor Signaling and G<sub>olf</sub>
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 Subtype in the Striatum<xref ref-type="fn" rid="FN1">*</xref>
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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>
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La maladie de Parkinson en France (serveur d'exploration)

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum*

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum*

Source :

Abstract

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