Glutathione and Signal Transduction in the Mammalian CNS

Abstract

Abstract:The tripeptide glutathione (GSH) has been thoroughly investigated in relation to its role as antioxidant and free radical scavenger. In recent years, novel actions of GSH in the nervous system have also been described, suggesting that GSH may serve additionally both as a neuromodulator and as a neurotransmitter. In the present article, we describe our studies to explore further a potential role of GSH as neuromodulator/neurotransmitter. These studies have used a combination of methods, including radioligand binding, synaptic release and uptake assays, and electrophysiological recording. We report 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 ␥-glutamyl moiety to ionotropic glutamate receptors. At micromolar concentrations GSH displaces excitatory agonists, acting to halt their physiological actions on target neurons. At millimolar concentrations, GSH, acting through its free cysteinyl thiol group, modulates the redox site of NMDA receptors. As such modulation has been shown to increase NMDA receptor channel currents, this action may play 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 amino acid receptor subtypes. GSH bound to these sites is not displaceable by glutamatergic agonists or antagonists. These binding sites, which we believe to be distinct receptor populations, appear to recognize the cysteinyl moiety 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 potential recordings in rat cerebral cortex that reveal a dose-dependent depolarization 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-isoxazolepropionate antagonists. The present data support a reevaluation of the role of 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 GSH may lead to more comprehensive understanding of synaptic function in normal and disease states.

Regulation of Neuronal Glutathione Synthesis

“…GSH binds via its gamma-glutamyl moiety to NMDA receptors (29). GSH is thought to exert dual (agonistic / antagonistic) actions on neuronal responses mediated by NMDA receptors in the brain.…”

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

“…The increased level of glutathione in the present study could point to a decreased use of antioxidants, possibly caused by diminished NO production due to lower Ca 2 + concentration and NMDA blockade. Interestingly, there is evidence that glutathione also enhances the NMDA receptor response to glutamate (Janaky et al, 1993). However, in cerebrospinal fluid of drug-free schizophrenic patients, a significant decrease in the level of glutathione was observed (Do et al, 2000).…”

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

“…A decreased glutathione level, through inhibition of its synthesis, is accompanied by increased excitotoxic response to NMDA, degeneration of mitochondria, and larger infarct areas in stroke models (20)(21)(22). Extracellularly, glutathione has been suggested to have multifaceted electrophysiological effects by binding to its own receptors and by modulating glutamatergic excitatory neurotransmission by displacing glutamate from its ionotropic receptors (23)(24)(25). Glutathione may also increase NMDA receptor responses by interacting with its redox sites (26)(27)(28).…”