Astrocytes and neurons: different roles in regulating adenosine levels
Astrocytes and neurons: different roles in regulating adenosine levels
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DOI：
10.1179/016164105x21878
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发表时间：
2005-03-01
影响因子：
1.9
通讯作者：
Zamzow, CR
中科院分区：
文献类型：
--
作者：
Parkinson, FE;Xiong, W;Zamzow, CR
目的：腺苷是一种内源性核苷，通过g蛋白偶联受体发出信号。细胞外腺苷是受体激活所必需的，腺苷的形成和细胞释放有两种途径。经典途径依赖于腺嘌呤核苷酸在细胞内形成腺苷和腺苷通过平衡核苷转运体（ENTs）的细胞外排。替代途径包括腺嘌呤核苷酸的细胞释放，通过外5'-核苷酸酶水解和腺苷的细胞外形成。方法：采用大鼠脑缺血模型和大鼠前脑星形胶质细胞和神经元原代培养。结果：在脑缺血大鼠模型中，与盐水处理相比，ENT1抑制剂硝基苄基甲基topurine核糖核苷(nitrobenzylmerca\topurine核糖核苷（NBMPR）显著增加缺血后前脑腺苷水平，显著减轻海马神经元损伤。未检测到nbmpr诱导的腺苷受体激活增加，提示改变细胞内和细胞外腺苷分布可影响缺血结局。利用大鼠前脑星形胶质细胞和神经元原代培养物，观察类缺血条件下腺苷的释放。双嘧达莫，一种ENTs抑制剂，在抑制腺苷从神经元释放比从星形胶质细胞释放更有效。相反，α， β -亚甲基ADP，一种外5′-核苷酸酶抑制剂，能有效抑制星形胶质细胞释放腺苷，但不能抑制神经元释放腺苷。因此，在类缺血条件下，神经元通过classic通路释放腺苷，而星形胶质细胞通过ALTERNATE通路释放腺苷。讨论：缺血期间腺苷形成途径的细胞类型差异可能允许转运抑制剂同时阻止腺苷从神经元释放和腺苷摄取到星形胶质细胞。原则上，这可以在不降低腺苷受体激活的情况下提高神经元ATP水平。
Objectives: Adenosine is an endogenous nucleoside that signals through G-protein coupled receptors. Extracellular adenosine is required for receptor activation and two pathways have been identified for formation and cellular release of adenosine. The CLASSICAL pathway relies on intracellular formation of adenosine from adenine nucleotides and cellular efflux of adenosine via equilibrative nucleoside transporters (ENTs). The ALTERNATE pathway involves cellular release of adenine nucleotides, hydrolysis via ecto-5'-nucleotidases and extracellular formation of adenosine.Methods: A rat model of cerebral ischemia and primary cultures of rat forebrain astrocytes and neurons were used.Results: Using a rat model of cerebral ischemia, the ENT1 inhibitor nitrobenzylmerca\topurine ribonucleoside (NBMPR) significantly increased post-ischemic forebrain adenosine revels and significantly decreased hippocampal neuron injury relative to saline-treatment. NBMPR-induced increases in adenosine receptor activation were not detected, suggesting that altering the intracellular:extracellular distribution of adenosine can affect ischemic outcome. Using primary cultures of rat forebrain astrocytes and neurons, adenosine release was evoked by ischemic-like conditions. Dipyridamole, an inhibitor of ENTs, was more effective at inhibiting adenosine release from neurons than from astrocytes. In contrast, alpha,beta-methylene ADP, an inhibitor of ecto-5'-nucleotidase, was effective at inhibiting adenosine release from astrocytes, but not from neurons. Thus, during ischemic-like conditions, neurons released adenosine via the CLASSICAL pathway, while astrocytes released adenosine via the ALTERNATE pathway.Discussion: These cell type differences in pathways for adenosine formation during ischemia may allow transport inhibitors to block simultaneously adenosine release from neurons and adenosine uptake into astrocytes. In principle, this could improve neuronal ATP levels without decreasing adenosine receptor activation.