Glutathione and signal transduction in the mammalian CNS

The tripeptide glutathione (GSH) has been thoroughly investigated in relati on to its role as antioxidant and free radical scavenger. In recent years, novel actions of GSH in the nervous system have also been described, sugges ting that GSH may serve additionally both as a neuromodulator and as a neur otransmitter. In the present article, we describe our studies to explore fu rther a potential role of GSH as neuromodulator/neurotransmitter. These stu dies have used a combination of methods, including radioligand binding, syn aptic release and uptake assays, and electrophysiological recording. We rep ort here the characteristics of GSH binding sites, the interrelationship of GSH with the NMDA receptor, and the effects of GSH on neural activity. Our results demonstrate that GSH binds via its gamma-glutamyl moiety to ionotr opic glutamate receptors. At micromolar concentrations GSH displaces excita tory agonists, acting to halt their physiological actions on target neurons . At millimolar concentrations, GSH, acting through its free cysteinyl thio l group, modulates the redox site of NMDA receptors, As such modulation has been shown to increase NMDA receptor channel currents, this action may pla y a significant role in normal and abnormal synaptic activity. In addition, GSH in the nanomolar to micromolar range binds to at least two populations of binding sites that appear to be distinct from all known excitatory amin o acid receptor subtypes. GSH bound to these sites is not displaceable by g lutamatergic agonists or antagonists. These binding sites, which we believe to be distinct receptor populations, appear to recognize the cysteinyl moi ety of the GSH molecule. Like NMDA receptors, the GSH binding sites possess a coagonist site(s) for allosteric modulation. Furthermore, they appear to be linked to sodium ionophores, an interpretation supported by field poten tial recordings in rat cerebral cortex that reveal a dose-dependent depolar ization to applied GSH that is blocked by the absence of sodium but not by lowering calcium or by NMDA or (S)-2-amino-3-hydroxy-5-methyl-4-isoxazolepr opionate antagonists. The present data support a reevaluation of the role o f GSH in the nervous system in which GSH may be involved both directly and indirectly in synaptic transmission. A full accounting of the actions of GS H may lead to more comprehensive understanding of synaptic function in norm al and disease states.