Cunha R A, Sebastião A M, Ribeiro J A
Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, 1600 Lisbon, Portugal.
J Neurosci. 1998 Mar 15;18(6):1987-95. doi: 10.1523/JNEUROSCI.18-06-01987.1998.
ATP analogs substituted in the gamma-phosphorus (ATPgammaS, beta, gamma-imido-ATP, and beta,gamma-methylene-ATP) were used to probe the involvement of P2 receptors in the modulation of synaptic transmission in the hippocampus, because their extracellular catabolism was virtually not detected in CA1 slices. ATP and gamma-substituted analogs were equipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC50 of 17-22 microM). The inhibitory effect of ATP and gamma-phosphorus-substituted ATP analogs (30 microM) was not modified by the P2 receptor antagonist suramin (100 microM), was inhibited by 42-49% by the ecto-5'-nucleotidase inhibitor and alpha,beta-methylene ADP (100 microM), was inhibited by 74-85% by 2 U/ml adenosine deaminase (which converts adenosine into its inactive metabolite-inosine), and was nearly prevented by the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 nM). Stronger support for the involvement of extracellular adenosine formation as a main requirement for the inhibitory effect of ATP and gamma-substituted ATP analogs was the observation that an inhibitor of adenosine uptake, dipyridamole (20 microM), potentiated by 92-124% the inhibitory effect of ATP and gamma-substituted ATP analogs (10 microM), a potentiation similar to that obtained for 10 microM adenosine (113%). Thus, the present results indicate that inhibition by extracellular ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases and channeling of the generated adenosine to adenosine A1 receptors.
在γ-磷位被取代的ATP类似物（ATPγS、β,γ-亚氨基-ATP和β,γ-亚甲基-ATP）被用于探究P2受体在海马体突触传递调节中的作用，因为在CA1脑片中几乎检测不到它们的细胞外分解代谢。ATP和γ-取代类似物在抑制CA1锥体突触的突触传递方面具有同等效力（IC50为17 - 22微摩尔）。ATP和γ-磷位取代的ATP类似物（30微摩尔）的抑制作用不受P2受体拮抗剂苏拉明（100微摩尔）的影响，被胞外5'-核苷酸酶抑制剂和α,β-亚甲基ADP（100微摩尔）抑制42 - 49%，被2单位/毫升的腺苷脱氨酶（将腺苷转化为其无活性代谢产物肌苷）抑制74 - 85%，并且几乎被腺苷A1受体拮抗剂1,3 - 二丙基 - 8 - 环戊基黄嘌呤（10纳摩尔）阻断。对细胞外腺苷形成作为ATP和γ-取代ATP类似物抑制作用主要条件的更强支持是观察到腺苷摄取抑制剂双嘧达莫（20微摩尔）使ATP和γ-取代ATP类似物（10微摩尔）的抑制作用增强92 - 124%，这种增强类似于10微摩尔腺苷所产生的增强（113%）。因此，目前的结果表明，细胞外ATP对海马体突触传递的抑制作用需要胞外核苷酸酶进行局部细胞外分解代谢，并将生成的腺苷导向腺苷A1受体。
