S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity.
Ontology highlight
ABSTRACT:
SUBMITTER: Tian J
PROVIDER: S-EPMC2492460 | biostudies-literature | 2008 Jul
REPOSITORIES: biostudies-literature
Publications
S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity.
Tian Jing J Kim Sangwon F SF Hester Lynda L Snyder Solomon H SH
Proceedings of the National Academy of Sciences of the United States of America 20080723 30
Glutamate/N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity involves cyclooxygenase (COX)-2. We demonstrate that this neurotoxicity reflects activation of COX-2 by S-nitrosylation after selective binding of neuronal nitric oxide synthase (nNOS) to COX-2. nNOS, via its PDZ domain, binds COX-2 with the generated NO S-nitrosylating and activating the enzyme. Selective disruption of nNOS-COX-2 binding prevents NMDA neurotoxicity. ...[more]
Similar Datasets
Project description:The altered function and/or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDAR-mediated toxicity is postulated to play a pivotal role.
| S-EPMC1413822 | biostudies-literature
Project description:Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKC? expression out of PKC isoforms. PKC? co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKC?. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKC?. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKC?, genetic inhibitions of PKC? [i.e., PKC? knockout mice (KO) and PKC? antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKC? is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKC? or p47phox, is important for dopaminergic protection against MA insult.
| S-EPMC7074955 | biostudies-literature
Project description:Tissue plasminogen activator (tPA) is the main activator of plasminogen into plasmin in the brain where it may have beneficial roles but also neurotoxic effects that could be plasmin dependent or not. Little is known about the substrates and pathways that mediate plasmin-independent tPA neurotoxicity. Here we show in primary hippocampal neurons that tPA promotes a catalytic-independent activation of the extracellular regulated kinase (Erk)1/2 signal transduction pathway through the N-methyl-D-aspartate receptor, G-proteins and protein kinase C. This results in GSK3 activation in a process that requires de novo synthesis of proteins, and leads to tau aberrant phosphorylation, microtubule destabilization and apoptosis. Similar effects are produced by amyloid aggregates in a tPA-dependent manner, as demonstrated by pharmacological treatments and in wt and tPA-/- mice neurons. Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau. This is the first demonstration of an intracellular pathway by which tPA triggers kinase activation, tau phosphorylation and neurotoxicity, suggesting a key role for this molecule in AD pathology.
| S-EPMC1142582 | biostudies-literature
Project description:S-nitrosylation of proteins by nitric oxide is a major mode of signalling in cells. S-nitrosylation can mediate the regulation of a range of proteins, including prominent nuclear proteins, such as HDAC2 (ref. 2) and PARP1 (ref. 3). The high reactivity of the nitric oxide group with protein thiols, but the selective nature of nitrosylation within the cell, implies the existence of targeting mechanisms. Specificity of nitric oxide signalling is often achieved by the binding of nitric oxide synthase (NOS) to target proteins, either directly or through scaffolding proteins such as PSD-95 (ref. 5) and CAPON. As the three principal isoforms of NOS--neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)--are primarily non-nuclear, the mechanisms by which nuclear proteins are selectively nitrosylated have been elusive. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is physiologically nitrosylated at its Cys 150 residue. Nitrosylated GAPDH (SNO-GAPDH) binds to Siah1, which possesses a nuclear localization signal, and is transported to the nucleus. Here, we show that SNO-GAPDH physiologically transnitrosylates nuclear proteins, including the deacetylating enzyme sirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2) and DNA-activated protein kinase (DNA-PK). Our findings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest that protein-protein transfer of nitric oxide groups may be a general mechanism in cellular signal transduction.
| S-EPMC2972384 | biostudies-literature
Project description:Dexras1, a small G-protein localized predominantly to the brain, is transcriptionally upregulated by the synthetic glucocorticoid dexamethasone. It has close homology to the Ras subfamily but differs in that Dexras1 contains an extended 7 kDa C-terminal tail. Previous studies in our laboratory showed that NMDA receptor activation, via NO and Dexras1, physiologically stimulates DMT1, the major iron importer. A membrane-permeable iron chelator substantially reduces NMDA excitotoxicity, suggesting that Dexras1-mediated iron influx plays a crucial role in NMDA/NO-mediated cell death. We here report that iron influx is elicited by nitric oxide but not by other proapoptotic stimuli, such as H₂O₂ or staurosporine. Deletion of Dexras1 in mice attenuates NO-mediated cell death in dissociated primary cortical neurons and retinal ganglion cells in vivo. Thus, Dexras1 appears to mediate NMDA-elicited neurotoxicity via NO and iron influx.
| S-EPMC3711661 | biostudies-literature
Project description:The interactive effects of HIV-1 infection and methamphetamine (METH) abuse in producing cognitive dysfunction represent a serious medical problem; however, the neural mechanisms underlying this interactive neurotoxicity remain elusive. In this study, we report that a combination of low, sub-toxic doses of METH + HIV-1 Tat 1-86 B, but not METH + HIV-1 gp120, directly induces death of rodent midbrain neurons in vitro. The effects of D1- and NMDA-receptor specific antagonists (SCH23390 and MK-801, respectively) on the neurotoxicity of different doses of METH or HIV-1 Tat alone and on the METH + HIV-1Tat interaction in midbrain neuronal cultures suggest that the induction of the cell death cascade by METH and Tat requires both dopaminergic (D1) and N-methyl D-aspartate (NMDA) receptor-mediated signaling. This interactive METH+Tat neurotoxicity does not occur in cultures of hippocampal neurons, which are predominately glutamatergic, express very low levels of dopamine receptors, and have no functional dopamine transporter (DAT). Thus, the presence of a subpopulation of neurons capable of dopamine release/uptake is essential for METH+Tat induction of the cell death cascade. Overall, our results support the hypothesis that METH and HIV-1 Tat disrupt the normal conjunction of signaling between D1 and NMDA receptors, resulting in neural dysfunction and death.
| S-EPMC4041990 | biostudies-literature
Project description:Opioid-induced hyperalgesia and analgesic tolerance can lead to dose escalation and inadequate pain treatment with μ-opioid receptor agonists. Opioids cause tonic activation of glutamate NMDA receptors (NMDARs) at primary afferent terminals, increasing nociceptive input. However, the signaling mechanisms responsible for opioid-induced activation of pre-synaptic NMDARs in the spinal dorsal horn remain unclear. In this study, we determined the role of MAPK signaling in opioid-induced pre-synaptic NMDAR activation caused by chronic morphine administration. Whole-cell recordings of excitatory post-synaptic currents (EPSCs) were performed on dorsal horn neurons in rat spinal cord slices. Chronic morphine administration markedly increased the frequency of miniature EPSCs, increased the amplitude of monosynaptic EPSCs evoked from the dorsal root, and reduced the paired-pulse ratio of evoked EPSCs. These changes were fully reversed by an NMDAR antagonist and normalized by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2), p38, or c-Jun N-terminal kinase (JNK). Furthermore, intrathecal injection of a selective ERK1/2, p38, or JNK inhibitor blocked pain hypersensitivity induced by chronic morphine treatment. These inhibitors also similarly attenuated a reduction in morphine's analgesic effect in rats. In addition, co-immunoprecipitation assays revealed that NMDARs formed a protein complex with ERK1/2, p38, and JNK in the spinal cord and that chronic morphine treatment increased physical interactions of NMDARs with these three MAPKs. Our findings suggest that opioid-induced hyperalgesia and analgesic tolerance are mediated by tonic activation of pre-synaptic NMDARs via three functionally interrelated MAPKs at the spinal cord level. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
| S-EPMC6340739 | biostudies-literature
Project description:Microglial cells are activated in response to different types of injuries or stress in the CNS. Such activation is necessary to get rid of the injurious agents and restore tissue homeostasis. However, excessive activation of microglial cells is harmful and contributes to secondary injury. Pertinently, microglial cell activity was targeted in many preclinical and clinical studies but such strategy failed in clinical trials. The main reason behind the failed attempts is the complexity of the injury mechanisms which needs either a combination therapy or targeting a process that is involved in multiple pathways. Cofilin is a cytoskeleton-associated protein involved in actin dynamics. In our previous study, we demonstrated the role of cofilin in mediating neuronal apoptosis during OGD conditions. Previous studies on microglia have shown the involvement of cofilin in ROS formation and phagocytosis. However, additional studies are needed to delineate the role of cofilin in microglial cell activation. Therefore, in the current study, we investigated the role of cofilin in LPS-induced microglial cell activation using cofilin siRNA knockdown paradigms. The viability of differentiated PC12 cells was used as a measure of the neurotoxic potential of conditioned medium derived from cofilin siRNA-transfected and LPS-activated microglial cells. Cofilin knockdown significantly inhibited LPS-induced microglial cell activation through NF-?B and JAK-STAT pathways. The release of proinflammatory mediators (NO, TNF-?, iNOS, and COX2) as well as microglial proliferation and migration rates were significantly reduced by cofilin knockdown. Furthermore, differentiated PC12 cells were protected from the neurotoxicity induced by conditioned medium derived from cofilin-transfected and LPS-activated microglial cells. In conclusion, we demonstrated that cofilin is involved in the cascade of microglial cell activation and further validates our previous study on cofilin's role in mediating neuronal apoptosis. Together, our results suggest that cofilin could present a common target in neurons and microglial cells and might prove to be a promising therapy for different brain injury mechanisms including stroke.
| S-EPMC5554748 | biostudies-other
Project description:Under ambient air conditions, NO inhibits NMDAR activity by reacting with the NR2A subunit C399 along with two additional cysteine pairs if their disulfide bonds are reduced to free thiol groups [NR1(C744,C798); NR2(C87,C320)]. Here we demonstrate that relative hypoxia enhances S-nitrosylation of NMDARs by a unique mechanism involving an "NO-reactive oxygen sensor motif" whose determinants include C744 and C798 of the NR1 subunit. Redox reactions involving these two thiol groups sensitize other NMDAR sites to S-nitrosylation and consequent receptor inhibition, while their own nitrosylation has little effect on NMDAR activity. The crystal structure of the ligand-binding domain of NR1 reveals a flexible disulfide bond (C744-C798), which may account for its susceptibility to reduction and subsequent reaction with NO that is observed with biochemical techniques. These thiols may be nitrosylated preferentially during increasing hypoxia or stroke conditions, thus preventing excessive activity associated with cytotoxicity while avoiding blockade of physiologically active NMDARs.
| S-EPMC1855274 | biostudies-literature
Project description:Membrane-associated guanylate kinases (MAGUKs) are the major family of scaffolding proteins at the postsynaptic density. The PSD-MAGUK subfamily, which includes PSD-95, PSD-93, SAP97, and SAP102, is well accepted to be primarily involved in the synaptic anchoring of numerous proteins, including N-methyl-D-aspartate receptors (NMDARs). Notably, the synaptic targeting of NMDARs depends on the binding of the PDZ ligand on the GluN2B subunit to MAGUK PDZ domains, as disruption of this interaction dramatically decreases NMDAR surface and synaptic expression. We recently reported a secondary interaction between SAP102 and GluN2B, in addition to the PDZ interaction. Here, we identify two critical residues on GluN2B responsible for the non-PDZ binding to SAP102. Strikingly, either mutation of these critical residues or knockdown of endogenous SAP102 can rescue the defective surface expression and synaptic localization of PDZ binding-deficient GluN2B. These data reveal an unexpected, nonscaffolding role for SAP102 in the synaptic clearance of GluN2B-containing NMDARs.
| S-EPMC3513525 | biostudies-literature