Janáky Réka, Dohovics Róbert, Saransaari Pirjo, Oja Simo S
Brain Research Center, University of Tampere Medical School, Tampere, Finland.
Neurochem Res. 2007 Aug;32(8):1357-64. doi: 10.1007/s11064-007-9315-z. Epub 2007 Mar 31.
Glutathione (gamma-glutamylcysteinylglycine, GSH and oxidized glutathione, GSSG), may function as a neuromodulator at the glutamate receptors and as a neurotransmitter at its own receptors. We studied now the effects of GSH, GSSG, glutathione derivatives and thiol redox agents on the spontaneous, K(+)- and glutamate-agonist-evoked releases of [(3)H]dopamine from mouse striatal slices. The release evoked by 25 mM K(+) was inhibited by GSH, S-ethyl-, -propyl-, -butyl- and pentylglutathione and glutathione sulfonate. 5,5'-Dithio-bis-2-nitrobenzoate (DTNB) and L-cystine were also inhibitory, while dithiothreitol (DTT) and L-cysteine enhanced the K(+)-evoked release. Ten min preperfusion with 50 microM ZnCl(2) enhanced the basal unstimulated release but prevented the activation of K(+)-evoked release by DTT. Kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) evoked dopamine release but the other glutamate receptor agonists N-methyl-D-aspartate (NMDA), glycine (1 mM) and trans-1-aminocyclopentane-1,3-dicarboxylate (t-ACPD, 0.5 mM), and the modulators GSH, GSSG, glutathione sulfonate, S-alkyl-derivatives of glutathione, DTNB, cystine, cysteine and DTT (all 1 mM) were without effect. The release evoked by 1 mM glutamate was enhanced by 1 mM GSH, while GSSG, glutathionesulfonate and S-alkyl derivatives of glutathione were generally without effect or inhibitory. NMDA (1 mM) evoked release only in the presence of 1 mM GSH but not with GSSG, other peptides or thiol modulators. L-Cysteine (1 mM) enhanced the glutamate-evoked release similarly to GSH. The activation by 1 mM kainate was inhibited by S-ethyl-, -propyl-, and -butylglutathione and the activation by 0.5 mM AMPA was inhibited by S-ethylglutathione but enhanced by GSSG. Glutathione alone does not directly evoke dopamine release but may inhibit the depolarization-evoked release by preventing the toxic effects of high glutamate, and by modulating the cysteine-cystine redox state in Ca(2+ )channels. GSH also seems to enhance the glutamate-agonist-evoked release via both non-NMDA and NMDA receptors. In this action, the gamma-glutamyl and cysteinyl moieties of glutathione are involved.
谷胱甘肽（γ-谷氨酰半胱氨酰甘氨酸，GSH以及氧化型谷胱甘肽，GSSG），可能在谷氨酸受体处作为神经调质发挥作用，并在其自身受体处作为神经递质发挥作用。我们现在研究了GSH、GSSG、谷胱甘肽衍生物以及硫醇氧化还原试剂对小鼠纹状体切片中[³H]多巴胺的自发释放、K⁺和谷氨酸激动剂诱发释放的影响。25 mM K⁺诱发的释放受到GSH、S-乙基、-丙基、-丁基和戊基谷胱甘肽以及谷胱甘肽磺酸盐的抑制。5,5'-二硫代双-2-硝基苯甲酸（DTNB）和L-胱氨酸也具有抑制作用，而二硫苏糖醇（DTT）和L-半胱氨酸则增强了K⁺诱发的释放。用50 μM ZnCl₂预灌注10分钟可增强基础非刺激释放，但可防止DTT对K⁺诱发释放的激活。海人酸和2-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）可诱发多巴胺释放，但其他谷氨酸受体激动剂N-甲基-D-天冬氨酸（NMDA）、甘氨酸（1 mM）和反式-1-氨基环戊烷-1,3-二羧酸（t-ACPD，0.5 mM）以及调节剂GSH、GSSG、谷胱甘肽磺酸盐、谷胱甘肽的S-烷基衍生物、DTNB、胱氨酸、半胱氨酸和DTT（均为1 mM）均无作用。1 mM谷氨酸诱发的释放被1 mM GSH增强，而GSSG、谷胱甘肽磺酸盐和谷胱甘肽的S-烷基衍生物通常无作用或具有抑制作用。1 mM NMDA仅在存在1 mM GSH时诱发释放，而在存在GSSG、其他肽或硫醇调节剂时则不诱发释放。L-半胱氨酸（1 mM）与GSH类似地增强了谷氨酸诱发的释放。1 mM海人酸的激活受到S-乙基、-丙基和-丁基谷胱甘肽的抑制，0.5 mM AMPA的激活受到S-乙基谷胱甘肽的抑制，但被GSSG增强。单独的谷胱甘肽不会直接诱发多巴胺释放，但可能通过防止高谷氨酸的毒性作用以及调节Ca²⁺通道中的半胱氨酸-胱氨酸氧化还原状态来抑制去极化诱发的释放。GSH似乎还通过非NMDA和NMDA受体增强谷氨酸激动剂诱发的释放。在这一作用中，谷胱甘肽的γ-谷氨酰和半胱氨酰部分参与其中。
