Ecto-5′-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions
Journal of Neuroscience. 2013-07-10; 33(28): 11390-11399
DOI: 10.1523/jneurosci.5817-12.2013
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Augusto E(1), Matos M, Sévigny J, El-Tayeb A, Bynoe MS, Müller CE, Cunha RA,
Chen JF.
Author information:
(1)Department of Neurology, Boston University School of Medicine, Boston, MA
02118, USA.
Adenosine is a neuromodulator acting through inhibitory A1 receptors (A1Rs) 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 A1Rs, 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.