Chéramy A, Godeheu G, L'Hirondel M, Glowinski J
INSERM U114, Collège de France, Paris, France.
J Pharmacol Exp Ther. 1996 Feb;276(2):616-25.
In the presence of magnesium, although ineffective alone, N-methyl-D-aspartate (NMDA, 10(-3) M plus glycine 10(-6) M) stimulated the release of [3H]-dopamine ([3H]-DA) continuously synthesized from [3H]-tyrosine when applied with ACh, the amplitude of the NMDA response being dependent on the ACh concentration. Experiments performed with nicotine, oxotremorine and the antagonists hexamethonium and atropine indicated that both muscarinic and nicotinic receptors are involved in the permissive effect of ACh on the NMDA response. Data obtained in the absence of magnesium or with increasing concentrations of magnesium revealed that the permissive effect of ACh on the NMDA-evoked release of [3H]-DA results from removal of the magnesium block of NMDA receptors. The NMDA-evoked release of [3H]-DA observed in the presence of ACh, nicotine or oxotremorine (10(-3) M) was blocked by either of the protein kinase C inhibitors staurosporine (10(-8) M) and chelerythrine (5 x 10(-7) M). However, these drugs were without effect on responses induced by ACh, nicotine or oxotremorine alone and by NMDA (10(-3) M, in the absence of magnesium). Supporting further the involvement of a protein kinase C activation in the permissive effects of ACh or the cholinergic agonists, NMDA (10(-3) M) stimulated the release of [3H]-DA in the presence of both magnesium and phorbol 12-myristate 13-acetate (10(-6) M) or 1 -oleoyl-2-acetyl-glycerol (10(-4) M), and the NMDA response was markedly potentiated by ionomycin (10(-7) M) used at a concentration that stimulated [3H]-DA release to about the same degree as ACh (10(-4) M). Therefore, besides their depolarizing action, ACh, nicotine and oxotremorine could eliminate the magnesium block of NMDA receptors by activation of protein kinase C.
在有镁存在的情况下，虽然N-甲基-D-天冬氨酸（NMDA，10⁻³ M加甘氨酸10⁻⁶ M）单独使用时无效，但与乙酰胆碱（ACh）一起应用时，它能刺激从[³H]-酪氨酸持续合成的[³H]-多巴胺（[³H]-DA）释放，NMDA反应的幅度取决于ACh的浓度。用尼古丁、氧化震颤素以及拮抗剂六甲铵和阿托品进行的实验表明，毒蕈碱型和烟碱型受体均参与了ACh对NMDA反应的允许作用。在无镁存在或镁浓度增加的情况下获得的数据显示，ACh对NMDA诱发的[³H]-DA释放的允许作用是由于去除了NMDA受体的镁阻断。在ACh、尼古丁或氧化震颤素（10⁻³ M）存在下观察到的NMDA诱发的[³H]-DA释放被蛋白激酶C抑制剂星形孢菌素（10⁻⁸ M）和白屈菜红碱（5×10⁻⁷ M）中的任何一种所阻断。然而，这些药物对单独由ACh、尼古丁或氧化震颤素以及由NMDA（10⁻³ M，在无镁情况下）诱导的反应没有影响。进一步支持蛋白激酶C激活参与ACh或胆碱能激动剂的允许作用的是，在镁和佛波醇12-肉豆蔻酸酯13-乙酸酯（10⁻⁶ M）或1-油酰-2-乙酰甘油（10⁻⁴ M）存在的情况下，NMDA（10⁻³ M）刺激了[³H]-DA的释放，并且离子霉素（10⁻⁷ M）以与ACh（10⁻⁴ M）刺激[³H]-DA释放程度大致相同的浓度使用时，显著增强了NMDA反应。因此，除了它们的去极化作用外，ACh、尼古丁和氧化震颤素可通过激活蛋白激酶C来消除NMDA受体的镁阻断。
