Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Glia. 2013 Oct;61(10):1595-606. doi: 10.1002/glia.22523. Epub 2013 Aug 6.
Extracellular adenosine 3',5'-cyclic monophosphate (3',5'-cAMP) is an endogenous source of localized adenosine production in many organs. Recent studies suggest that extracellular 2',3'-cAMP (positional isomer of 3',5'-cAMP) is also a source of adenosine, particularly in the brain in vivo post-injury. Moreover, in vitro studies show that both microglia and astrocytes can convert extracellular 2',3'-cAMP to adenosine. Here, we examined the ability of primary mouse oligodendrocytes and neurons to metabolize extracellular 2',3'-cAMP and their respective adenosine monophosphates (2'-AMP and 3'-AMP). Cells were also isolated from mice deficient in 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). Oligodendrocytes metabolized 2',3'-cAMP to 2'-AMP with 10-fold greater efficiency than did neurons (and also more than previously examined microglia and astrocytes); whereas, the production of 3'-AMP was minimal in both oligodendrocytes and neurons. The production of 2'-AMP from 2',3'-cAMP was reduced by 65% in CNPase -/- versus CNPase +/+ oligodendrocytes. Oligodendrocytes also converted 2'-AMP to adenosine, and this was also attenuated in CNPase -/- oligodendrocytes. Inhibition of classic 3',5'-cAMP-3'-phosphodiesterases with 3-isobutyl-1-methylxanthine did not block metabolism of 2',3'-cAMP to 2'-AMP and inhibition of classic ecto-5'-nucleotidase (CD73) with α,β-methylene-adenosine-5'-diphosphate did not attenuate the conversion of 2'-AMP to adenosine. These studies demonstrate that oligodendrocytes express the extracellular 2',3'-cAMP-adenosine pathway (2',3'-cAMP → 2'-AMP → adenosine). This pathway is more robustly expressed in oligodendrocytes than in all other CNS cell types because CNPase is the predominant enzyme that metabolizes 2',3'-cAMP to 2-AMP in CNS cells. By reducing levels of 2',3'-cAMP (a mitochondrial toxin) and increasing levels of adenosine (a neuroprotectant), oligodendrocytes may protect axons from injury.
细胞外腺苷 3',5'-环单磷酸（3',5'-cAMP）是许多器官中局部腺苷产生的内源性来源。最近的研究表明，细胞外 2',3'-cAMP（3',5'-cAMP 的位置异构体）也是腺苷的来源，特别是在体内损伤后的大脑中。此外，体外研究表明小胶质细胞和星形胶质细胞都可以将细胞外 2',3'-cAMP 转化为腺苷。在这里，我们检查了原代小鼠少突胶质细胞和神经元代谢细胞外 2',3'-cAMP 及其各自的腺苷单磷酸（2'-AMP 和 3'-AMP）的能力。还从小鼠中分离出缺乏 2',3'-环核苷酸-3'-磷酸二酯酶（CNPase）的细胞。与神经元相比，少突胶质细胞将 2',3'-cAMP 代谢为 2'-AMP 的效率高 10 倍（也高于之前检查过的小胶质细胞和星形胶质细胞）；而 3'-AMP 的产生在少突胶质细胞和神经元中都很少。CNPase -/- 与 CNPase +/+ 少突胶质细胞相比，2',3'-cAMP 生成 2'-AMP 的产量减少了 65%。少突胶质细胞还将 2'-AMP 转化为腺苷，而 CNPase -/- 少突胶质细胞中的这种转化也减弱了。用 3-异丁基-1-甲基黄嘌呤抑制经典 3',5'-cAMP-3'-磷酸二酯酶不会阻断 2',3'-cAMP 代谢为 2'-AMP，用 α,β-亚甲基-腺苷-5'-二磷酸抑制经典外切 5'-核苷酸酶（CD73）也不会减弱 2'-AMP 转化为腺苷。这些研究表明，少突胶质细胞表达细胞外 2',3'-cAMP-腺苷途径（2',3'-cAMP → 2'-AMP → 腺苷）。与所有其他中枢神经系统细胞类型相比，该途径在少突胶质细胞中的表达更为强烈，因为 CNPase 是将 2',3'-cAMP 代谢为 2-AMP 的主要酶。通过降低 2',3'-cAMP（线粒体毒素）的水平和增加腺苷（神经保护剂）的水平，少突胶质细胞可能会保护轴突免受损伤。
