Deletion of Ecto-5′-Nucleotidase (CD73) Reveals Direct Action Potential-Dependent Adenosine Release
Deletion of Ecto-5′-Nucleotidase (CD73) Reveals Direct Action Potential-Dependent Adenosine Release
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DOI：
10.1523/jneurosci.6052-11.2012
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发表时间：
2012-03-14
影响因子：
5.3
通讯作者：
Wall, Mark J.
中科院分区：
文献类型：
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作者：
Klyuch, Boris P.;Dale, Nicholas;Wall, Mark J.
嘌呤能信号是一个高度复杂的细胞外通讯系统，参与哺乳动物脑内许多生理和病理功能。其复杂性源于嘌呤受体亚型和内源性嘌呤受体配体（包括ATP、ADP、UTP、UDP和腺苷）的多样性。潜在地，所有这些配体都可以直接释放，并且一些配体也可以由细胞外代谢产生。广泛持有的共识是，除了在病理条件下，细胞外腺苷只产生于胞外ATP酶介导的代谢先前释放的ATP。在这里，我们使用了缺乏CD 73基因（编码将AMP转化为腺苷的外-5 '-核苷酸酶）的小鼠来测试小脑中动作电位依赖性腺苷释放是否依赖于先前的ATP释放。令人惊讶的是，我们已经发现了两个平行的腺苷释放途径：一个是间接的，通过谷氨酸受体依赖性释放ATP和第二个相同的幅度，没有依赖于先前释放的ATP，因此代表腺苷的直接释放。腺苷释放的这一组分被巴弗洛霉素阻断，并被mGlu 4受体激活调节，强烈支持腺苷通过平行纤维的胞吐作用释放。我们的发现是了解腺苷释放机制的重要一步，并可能对腺苷发挥关键调节作用的生理学的各个方面产生影响。
Purinergic signaling is a highly complex system of extracellular communication involved in many physiological and pathological functions in the mammalian brain. Its complexity stems from the multitude of purine receptor subtypes and endogenous purine receptor ligands (including ATP, ADP, UTP, UDP, and adenosine). Potentially all of these ligands could be directly released, and some could also arise from extracellular metabolism. Awidely held consensus is that, except under pathological conditions, extracellular adenosine arises only from ectoATPase-mediated metabolism of previously released ATP. Here, we have used mice that lack the CD73 gene (encoding ecto-5'-nucleotidase that converts AMP to adenosine) to test whether action potential-dependent adenosine release in the cerebellum depends on prior ATP release. Surprisingly, we have uncovered two parallel pathways of adenosine release: one that is indirect via glutamate receptor-dependent release of ATP and a second of equal amplitude that has no dependence on prior release of ATP and thus represents the direct release of adenosine. This component of adenosine release is blocked by bafilomycin and modulated by mGlu4 receptor activation, strongly supporting adenosine release by exocytosis from parallel fibers. Our findings are a major step in understanding the mechanisms of adenosine release and are likely to have implications for all aspects of physiology where adenosine plays a key modulatory role.