Janáky R, Varga V, Oja S S, Saransaari P
Tampere Brain Research Center, Department of Biomedical Sciences, University of Tampere, Finland.
Neurochem Int. 1994 Jun;24(6):575-82. doi: 10.1016/0197-0186(94)90010-8.
The effects of dithiothreitol (DTT) and, reduced (GSH) and oxidized (GSSG), glutathione on the release of [3H]GABA evoked by glutamate and its agonists were studied in rat hippocampal slices. DTT had no effect on the basal release of [3H]GABA but it enhanced and prolonged the glutamate agonist-evoked release. This effect was abolished by (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohept-5,10-imine hydrogen maleate (MK-801), a noncompetitive NMDA antagonist, and blocked by Mg2+ ions. It was only slightly attenuated by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, and not affected by L-(+)-2-amino-3-phosphonopropionate (L-AP3), a selective antagonist of the metabotropic glutamate receptor. The effect of DTT on the NMDA-evoked release of GABA was only slightly affected by extracellular Ca2+ but completely blocked by verapamil even in the absence of Ca2+. GSH and GSSG attenuated or abolished the effects of DTT on the agonist-induced release of [3H]GABA. The results imply that the enhanced and prolonged release of GABA evoked by the coexistence of DTT and excitatory amino acids and attenuated by endogenous GSH and GSSG is a consequence of sustained activation of the NMDA receptor-governed ionophores, which contain functional thiol groups. DTT, GSH and GSSG may regulate the redox state and accessibility of these groups. In addition to the influx of extracellular Ca2+, DTT mobilizes Ca2+ from intracellular pools distinct from those regulated by metabotropic glutamate receptors.
在大鼠海马切片中，研究了二硫苏糖醇（DTT）、还原型谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）对谷氨酸及其激动剂诱发的[3H]GABA释放的影响。DTT对[3H]GABA的基础释放没有影响，但它增强并延长了谷氨酸激动剂诱发的释放。这种作用被非竞争性NMDA拮抗剂马来酸（+）-5-甲基-10,11-二氢-5H-二苯并（a,d）环庚-5,10-亚胺（MK-801）消除，并被Mg2+离子阻断。它仅被非NMDA受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）轻微减弱，而不受代谢型谷氨酸受体的选择性拮抗剂L-（+）-2-氨基-3-膦酰丙酸（L-AP3）的影响。DTT对NMDA诱发的GABA释放的作用仅受到细胞外Ca2+的轻微影响，但即使在没有Ca2+的情况下也被维拉帕米完全阻断。GSH和GSSG减弱或消除了DTT对激动剂诱导的[3H]GABA释放的作用。结果表明，DTT与兴奋性氨基酸共存诱发的GABA增强和延长释放以及内源性GSH和GSSG减弱的释放是NMDA受体介导的离子通道持续激活的结果，这些离子通道含有功能性硫醇基团。DTT、GSH和GSSG可能调节这些基团的氧化还原状态和可及性。除了细胞外Ca2+的内流，DTT还从不同于代谢型谷氨酸受体调节的细胞内池动员Ca2+。
