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- Title
Ecto-5'-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A<sub>2A</sub> Receptor Functions.
- Authors
Augusto, Elisabete; Matos, Marco; Sévigny, Jean; El-Tayeb, Ali; Bynoe, Margaret S.; Müller, Christa E.; Cunha, Rodrigo A.; Chen, Jiang-Fan
- Abstract
Adenosine is a neuromodulator acting through inhibitory A, receptors (A,Rs) and facilitatory A2ARs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A,Rs, but the source of the adenosine activating A2ARs is unknown. We now show that ecto-5'-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A2ARS in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A2ARS and proximity ligation assays confirmed the close proximity of CD73 and A2ARS in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A2AR prodrug that requires CD73 metabolization to activate A2ARS were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A2AR KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A2AR KO mice, as well as upon pharmacological A2AR blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A2AR function. This study points to CD73 as a new target that can fine-tune A2AR activity, and a novel therapeutic target to manipulate A2AR-mediated control of striatal function and neurodegeneration.
- Subjects
NUCLEOTIDASES; ADENOSINES; GROWTH associated protein-43; INTRACELLULAR membranes; ADENOSINE kinase; EXTRACELLULAR enzymes; LABORATORY mice
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 28, p11390
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5817-12.2013