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首页> 外文期刊>The European Journal of Neuroscience >NMDA receptor-mediated extracellular adenosine accumulation in rat forebrain neurons in culture is associated with inhibition of adenosine kinase.
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NMDA receptor-mediated extracellular adenosine accumulation in rat forebrain neurons in culture is associated with inhibition of adenosine kinase.

机译：在培养中的大鼠前脑神经元中，NMDA受体介导的细胞外腺苷蓄积与腺苷激酶的抑制有关。

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The effect of N-methyl-d-aspartate (NMDA) on regulation of extracellular adenosine was investigated in rat forebrain neurons in culture. NMDA evoked accumulation of extracellular adenosine with an EC50 value of 4.8 +/- 1.2 micro m. The effect of NMDA was blocked by (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate indicating that NMDA receptor activation was involved. The NMDA effect was also blocked by chelation of extracellular Ca2+ indicating that influx of calcium was required. The nitric oxide-cyclic GMP signalling pathway was not involved, as nitric oxide synthase inhibitors were unable to block, and cGMP analogs were unable to mimic, the effect of NMDA. The source for extracellular adenosine was likely to be intracellular adenosine as the ecto-5'-nucleotidase inhibitor alphabeta-methylene-ADP was unable to block the effect of NMDA. One possible cause of intracellular adenosine accumulation might be NMDA receptor-mediated inhibition of mitochondrial function andATP hydrolysis. We found that NMDA caused a concentration dependent depletion of intracellular ATP with an EC50 value of 21 +/- 8 micro m. NMDA also caused a significant decrease in adenosine kinase activity, assayed by two different methods. Consistent with the hypothesis that inhibition of adenosine kinase is sufficient to cause an increase in extracellular adenosine, inhibition of adenosine kinase by 5'-iodotubercidin resulted in elevation of extracellular adenosine. However, in the presence of a concentration of 5'-iodotubercidin that inhibited over 90% of adenosine kinase activity, exposure to NMDA still caused adenosine accumulation. These studies suggest that several possible mechanisms are likely to be involved in NMDA-evoked extracellular adenosine accumulation.
机译：在培养的大鼠前脑神经元中研究了N-甲基-d-天冬氨酸（NMDA）对细胞外腺苷调节的影响。 NMDA引起细胞外腺苷的积累，EC50值为4.8 +/- 1.2微米。 NMDA的作用被（+）-5-甲基-10,11-二氢-5H-二苯并[a，d]环庚-5,10-亚胺马来酸氢盐阻断，表明涉及NMDA受体活化。 NMDA的作用也被细胞外Ca2 +的螯合作用所阻断，表明需要钙的流入。由于一氧化氮合酶抑制剂无法阻断，cGMP类似物也无法模仿NMDA的作用，因此不涉及一氧化氮循环GMP信号通路。细胞外腺苷的来源可能是细胞内腺苷，因为ecto-5'-核苷酸酶抑制剂字母a-亚甲基-ADP无法阻断NMDA的作用。细胞内腺苷积累的一种可能原因可能是NMDA受体介导的线粒体功能抑制和ATP水解。我们发现NMDA导致浓度依赖性的细胞内ATP消耗，EC50值为21 +/- 8微米。用两种不同的方法测定，NMDA也引起腺苷激酶活性的显着降低。与腺苷激酶的抑制足以引起细胞外腺苷增加的假设相一致，5'-碘杜比西丁对腺苷激酶的抑制导致细胞外腺苷升高。但是，在浓度超过抑制90％的腺苷激酶活性的5'-碘杜布西丁存在下，暴露于NMDA仍会引起腺苷积聚。这些研究表明，NMDA引起的细胞外腺苷积累可能涉及几种可能的机制。

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