Ecto-5′-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions
Ecto-5′-Nucleotidase (CD73)-Mediated Formation of Adenosine Is Critical for the Striatal Adenosine A2A Receptor Functions
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DOI：
10.1523/jneurosci.5817-12.2013
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发表时间：
2013-07-10
影响因子：
5.3
通讯作者：
Chen, Jiang-Fan
中科院分区：
文献类型：
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作者：
Augusto, Elisabete;Matos, Marco;Chen, Jiang-Fan
腺苷是一种神经调节剂，通过抑制性a(1)受体（a (1)Rs）和促进性a (2A)Rs发挥作用，这两种受体对腺苷具有相似的亲和力。研究表明，胞内腺苷激酶的活性优先控制A(1)Rs的激活，但腺苷激活A(2A)Rs的来源尚不清楚。我们现在表明，能够将细胞外AMP转化为腺苷的主要酶外5′-核苷酸酶（CD73）与基底神经节中的A(2A)Rs共定位。除了星形胶质细胞外，纹状体CD73也明显定位于突触后部位。值得注意的是，CD73与A(2A)Rs共免疫沉淀，邻近结扎试验证实了纹状体中CD73和A(2A)Rs的密切邻近。因此，在野生型小鼠中观察到突触体中cAMP的形成以及由一种需要CD73代谢来激活a (2A)Rs的新型a (2A)R前药诱导的低运动，而在CD73敲除（KO）小鼠或a (2A)R KO小鼠中没有观察到。此外，CD73 KO小鼠表现出增加的工作记忆表现和减弱的安非他明诱导的敏化，模仿全局或前脑a (2A)R KO小鼠的表型，以及药理学a (2A)R阻断。这些结果表明，cd73介导的细胞外腺苷的形成是激活纹状体A(2A)R功能的原因。本研究指出CD73是一个可以微调a (2A)R活性的新靶点，也是一个操纵a (2A)R介导的纹状体功能和神经变性控制的新治疗靶点。
Adenosine is a neuromodulator acting through inhibitory A(1) receptors (A(1)Rs) and facilitatory A(2A)Rs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A(1)Rs, but the source of the adenosine activating A(2A)Rs is unknown. We now show that ecto-5'-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A(2A)Rs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A(2A)Rs and proximity ligation assays confirmed the close proximity of CD73 and A(2A)Rs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A(2A)R prodrug that requires CD73 metabolization to activate A(2A)Rs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A(2A)R KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A(2A)R KO mice, as well as upon pharmacological A(2A)R blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A(2A)R function. This study points to CD73 as a new target that can fine-tune A(2A)R activity, and a novel therapeutic target to manipulate A(2A)R-mediated control of striatal function and neurodegeneration.