Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor

Sullivan, Jane; Traynelis, Stephen F.; Chen, Huei Sheng Vincent; Escobar, Walter A.; Heinemann, Stephen F.; Lipton, Stuart A.

doi:10.1016/0896-6273(94)90258-5

Cited by 238 publications

(217 citation statements)

References 35 publications

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“…As observed here, L-lactate (but not L-pyruvate) metabolism gives rise to an intracellular increase of the NADH/NAD ratio, hence modifying the intracellular neuronal redox state. Redox-sensitive NMDA regulatory sites are present on the NR1 subunit, which favors NMDAR activity when in a reduced state and decreases its activity when oxidized, as demonstrated in particular with the use of DTT and 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) (21,22). Interestingly, we observed that the stimulatory effect of L-lactate on IEG expression is prevented in the presence of the oxidizing agent DTNB (Fig.…”

Section: Discussionmentioning

confidence: 64%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

404

373

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L-lactate is a product of aerobic glycolysis that can be used by neurons as an energy substrate. Here we report that in neurons L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, c-Fos, and Zif268 through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2. L-lactate potentiates NMDA receptor-mediated currents and the ensuing increase in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH, thereby modulating the redox state of neurons. NADH mimics all of the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. The induction of plasticity genes is observed both in mouse primary neurons in culture and in vivo in the mouse sensory-motor cortex. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long-term memory and long-term potentiation in vivo. This set of data reveals a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity.brain energy metabolism | learning and memory | astrocyte-neuron interaction | astrocyte-neuron lactate shuttle T he transfer of L-lactate from astrocytes to neurons was recently shown to be necessary for the establishment of longterm memory (LTM) in an inhibitory avoidance (IA) paradigm and for the maintenance of in vivo long-term potentiation (LTP) in the rodent hippocampus (1). This key role of L-lactate in neuronal plasticity mechanisms was demonstrated in experiments in which specific pharmacological and gene expression down-regulation interventions were implemented to prevent the production of L-lactate from glycogen-which is exclusively localized in astrocytes-and its release from these cells in the hippocampus during behavioral training (1). Such interventions completely prevented the establishment of LTM and their effect was fully reversed by the intrahippocampal administration of L-lactate during the training session. The fact that glucose at equicaloric concentrations only marginally mimicked the rescuing effect of L-lactate was taken as an unexpected indication that the primary mechanism of action of L-lactate on plasticity mechanisms was independent of its ability to act as an energy substrate. A role of L-lactate in memory processes was also recently shown in other behavioral paradigms (2, 3). We therefore set out to investigate the molecular mechanisms at the basis of the function of L-lactate on neuronal plasticity.Molecular mechanisms underlying both LTM and long-term plasticity include the induction of expression of a group of immediate early genes (IEGs) such as early growth response 1 (Zif268 or Egr1), CCAAT/enhancer binding protein (C/EBP), and proto-oncogene c-Fos (c-Fos) as well as activity-regulated cytoskeletal-associated protein (Arc or Arg3.1) as a direct effector protein at the synapse, which all participate to different physiological processes associated with neuronal p...

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Section: Discussionmentioning

confidence: 64%

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Yang

Ruchti

Petit

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

404

373

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“…Most importantly, cysteine residues in similar motifs to that described below for the NMDA receptor have been shown by various chemical criteria to be nitrosylated on proteins such as hemoglobin, p21 ras , cyclooxygenase and others. 2 As discussed above, two cysteines (abbreviated C in the single letter amino acid code) in the NR1 subunit have been found by site-directed mutagenesis to be necessary for the persistent component of redox modulation of that receptor 38 and in the reduced state they can be S-nitrosylated (Choi et al, submitted). Unexpectedly, however, these cysteines, C744 and C798, appear to be conserved in all ionotropic glutamate receptors when the sequences are aligned by overall homology.…”

Section: Proposed Consensus Motif For S-nitrosylationmentioning

confidence: 99%

“…Our work on nitrosylation and other redox reactions of recombinant NMDA receptors in the Xenopus oocyte expression system is instructive but also must be interpreted with a degree of caution. 38,41 We do not yet appreciate how to form recombinant NMDA receptors that exactly mimic native receptors and therefore conclusions based on site-directed mutagenesis studies of cysteine residues must be viewed with tempered enthusiasm. In fact, in the course of performing PCR reactions based on primers containing the cysteines known to be unique to NMDA receptor subunits, our group discovered a new NMDA receptor subunit (originally termed NMDAR-L or w 71 , but more recently named NR3A).…”

Section: S-nitrosylation Of Recombinant Nmda Receptorsmentioning

confidence: 99%

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Neuronal protection and destruction by NO

1999

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Nitric oxide (NO)-related species include different redox states of the NO group, which have recently been reported to exist endogenously in biological tissues including the brain. The importance of these different NO-related species is that their distinct chemical reactivities can influence the life and death of neurons in response to various insults. In the case of NO + equivalents (having one less electron than NO . ), the mechanism of reaction often involves Snitrosylation or transfer of the NO group to the sulfhydryl of a cysteine residue (or more properly to a thiolate anion) to form an RS-NO; further oxidation of critical thiols can possibly then form disulfide bonds from neighboring cysteine residues. We have mounted both physiological and chemical evidence that N-methyl-D-aspartate receptor (NMDAR) activity and caspase enzyme activity can be decreased by S-nitrosylation, as can other signaling molecules involved in neuronal apoptotic pathways, to afford neuroprotection. Over the past 5 years, beginning with our report on the NMDAR, evidence has accumulated that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. Thus, this chemical reaction is gaining acceptance as a newly-recognized molecular switch to control protein function via reactive thiol groups, such as those encountered on the NMDAR and in the active site of caspases. One method of producing S-nitrosylation of the NMDAR and caspases is the administration of nitroglycerin, and nitroglycerin can be neuroprotective in acute focal ischemia/reperfusion models via mechanisms other than increasing cerebral blood flow. In contrast, NO . itself does not appear to react with thiol under physiological conditions. In fact, the favored reaction of NO . is with O 2 .7 (superoxide anion) to form ONOO 7 (peroxynitrite), which can lead to neurotoxicity. A third NO-related species with one added electron compared to NO . is nitroxyl anion (NO 7 ). NO 7 ± unlike NO . but reminiscent of NO + transfer ± reacts with critical thiol groups of the NMDA receptor to curtail excessive Ca 2+ influx and thus provide neuroprotection from excitotoxic insults.

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“…Likewise, high-affinity inhibition by the non-competitive antagonist ifenprodil is dependent on the presence of NR2B although the binding site is different from the spermine site (Gallagher et al 1996). Redox-modulation of NMDA receptor responses is also affected by the receptor subunits present (Sullivan et al 1994;Grimwood et al 1996). NR2 subunits are consequently major determinants of NMDA receptor characteristics, and the distribution pattern of each subunit corresponds to particular features of the native receptors (Buller et al 1994;Monyer et al 1994) which forms the molecular basis for regional receptor heterogeneity.…”

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confidence: 99%

Polyamine and Redox Modulation of [³H]MK‐801 Binding to N‐Methyl‐d‐aspartate Receptors in the Spinal Cord and Cerebral Cortex

Sundström

2001

Pharmacology & Toxicology

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Abstract:The pharmacology of N-methyl--aspartate (NMDA) receptors shows regional differences in affinity for various agonists and antagonists. We have investigated the modulatory mechanisms acting via the polyamine, redox and proton sites in the cerebral cortex and the spinal cord of adult, male rats using [ 3 H]MK-801 binding. The affinity for glycineindependent spermine stimulation was one magnitude higher in cerebrocortical than in spinal cord membranes while the affinity for the spermine antagonist arcaine was similar. Spermine abolished the inhibiting effect of low pH in both regions. Thus, the difference in the polyamine site between the two regions seems to be restricted to agonist binding. The proportion of high affinity/total ifenprodil binding was ∑35% both in the spinal cord and the cerebral cortex, suggesting similar relative amounts of the NMDA receptor subunit 2B. The affinity of ifenprodil to the high affinity site was however significantly higher in the cerebral cortex. Redox modulatory agents had similar effects in the two regions but spermine fully counteracted the inhibiting effect of 0.2 mM 5,5ø-dithio-bis(2-nitrobenzoic acid) (DTNB) in the cerebral cortex while there was only a partial effect in the spinal cord. These data show that the regional pharmacological heterogeneity involves several of the mechanisms regulating the function of the NMDA receptor. The data also indicate that the NMDA receptor subunit 2B is much more common in spinal cord than previously suggested.

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Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor

Cited by 238 publications

References 35 publications

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Neuronal protection and destruction by NO

Polyamine and Redox Modulation of [³H]MK‐801 Binding to N‐Methyl‐d‐aspartate Receptors in the Spinal Cord and Cerebral Cortex

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Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor

Cited by 238 publications

References 35 publications

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons

Neuronal protection and destruction by NO

Polyamine and Redox Modulation of [3H]MK‐801 Binding to N‐Methyl‐d‐aspartate Receptors in the Spinal Cord and Cerebral Cortex

Contact Info

Product

Resources

About

Polyamine and Redox Modulation of [³H]MK‐801 Binding to N‐Methyl‐d‐aspartate Receptors in the Spinal Cord and Cerebral Cortex