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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have identified at least two homologous mitogen-activated protein (MAP) kinases that are activated by phosphorylation of both tyrosine and threonine residues by an activator kinase. To help define the role of these MAP kinases in neuronal signalling, we have used primary cultures derived from fetal rat cortex to assess the regulation of their activity by agonist stimulation of glutamate receptors and by synaptic activity. Regulation was assayed by monitoring changes in both tyrosine phosphorylation on western blots and in vitro kinase activity toward a selective MAP kinase substrate peptide. In initial studies, we found that phorbol ester treatment increased tyrosine phosphorylation of p42 MAP kinase and stimulated MAP kinase activity. A similar response was elicited by three agonists of metabotropic glutamate receptors, i.e., trans-(+/-)-1-amino-1,3-cyclopentane dicarboxylic acid, quisqualate, and (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine. MAP kinase activity and p42 MAP kinase tyrosine phosphorylation were also stimulated by the ionotropic glutamate receptor agonist, kainate, but not by N-methyl-D-aspartate. To examine regulation of MAP kinase by synaptic activity, cultures were treated with picrotoxin, an inhibitor of GABAA receptor-mediated inhibition that enhances spontaneous excitatory synaptic activity. Treatment of cultures with picrotoxin elicited activation of MAP kinase. This response was blocked by tetrodotoxin, which suppresses synaptic activity. These results demonstrate that p42 MAP kinase is activated by glutamate receptor agonist stimulation and by endogenous synaptic activity.
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PMID:Activation of p42 mitogen-activated protein kinase by glutamate receptor stimulation in rat primary cortical cultures. 769 64

MIN6 is one of the few pancreatic beta cell lines that respond to physiological concentrations of glucose by secreting insulin, and little is known about the triggered molecular mechanisms. We report below that the response to glucose in the MIN6 cells includes an activation of the p42 and p44 mitogen-activated protein (MAP) kinases (ERK2 and ERK1). This activation also occurred with the antidiabetic sulfonylurea glibenclamide and kainate, a specific agonist of a subtype of the ionotropic glutamate receptors, which depolarize the cytoplasmic membrane. The requirement for a calcium entry through the L-type voltage-gated channels and other characteristics of the regulation of the MAP kinase activity, such as the effect of the elevation of the cAMP concentration by forskolin, were similar to those of the secretion of insulin. However, the activation of the MAP kinases is not required for the secretion of insulin, inasmuch as this effect of glucose was not abolished when the MAP kinases were prevented from activation by PD098059, an inhibitor of the MAP kinase kinase. However, as the MAP kinases were translocated into the nucleus, they might be implicated in the calcium-dependent transcriptional response of the cells to glucose and thus regulate the expression of the insulin gene.
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PMID:Rapid activation and nuclear translocation of mitogen-activated protein kinases in response to physiological concentration of glucose in the MIN6 pancreatic beta cell line. 962 38

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The ionotropic glutamate receptors are classified into two groups, NMDA (N-methyl-D-aspartate) receptors and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors. The AMPA receptor is a ligand-gated cation channel that mediates the fast component of excitatory postsynaptic currents in the central nervous system. Here we report that AMPA receptors function not only as ion channels but also as cell-surface signal transducers by means of their interaction with the Src-family non-receptor protein tyrosine kinase Lyn. In the cerebellum, Lyn is physically associated with the AMPA receptor and is rapidly activated following stimulation of the receptor. Activation of Lyn is independent of Ca2+ and Na+ influx through AMPA receptors. As a result of activation of Lyn, the mitogen-activated protein kinase (MAPK) signalling pathway is activated, and the expression of brain-derived neurotrophic factor (BDNF) messenger RNA is increased in a Lyn-kinase-dependent manner. Thus, AMPA receptors generate intracellular signals from the cell surface to the nucleus through the Lyn-MAPK pathway, which may contribute to synaptic plasticity by regulating the expression of BDNF.
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PMID:The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. 989 56

Oligodendroglial cells express ionotropic glutamate receptors of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA) and kainate (KA) subtypes. Recently, we reported that AMPA receptor agonists increased 45Ca2+ uptake and phospholipase C (PLC) activity. To further elucidate the intracellular signaling mechanisms, we examined the effects of AMPA and KA on mitogen-activated protein kinase (MAPK). KA caused a time- and concentration-dependent increase in MAPK activity (predominantly the p42mapk or ERK2) and the effect was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a competitive AMPA/KA receptor antagonist. Furthermore, the noncompetitive antagonists of AMPA receptor GYKI 52466 and LY 303070 prevented the actions of the agonists, indicating that the effect of KA on MAPK activation is mediated through AMPA receptors in oligodendrocyte progenitors. Chelation of extracellular Ca2+ by EDTA or inhibition of PLC with U73122 abolished MAPK activation by KA. In addition, KA-stimulated MAPK activation was reduced by the protein kinase C (PKC) inhibitors, H7 and bisindolylmaleimide, as well as downregulation of PKC by prolonged exposure to phorbol esters. The involvement of PKC in the signal transduction pathways was further supported by the ability of KA to induce translocation of PKC measured by [3H]PDBu binding. Interestingly, a wortmannin-sensitive phosphatidylinositol 3-kinase and a pertussis toxin (PTX)-sensitive G protein form part of the molecular pathways mediating MAPK activation by AMPA receptor. A specific inhibitor of MAPK kinase, PD 098059, blocked MAPK activation and reduced KA-induced c-fos gene expression. All together, these results indicate that MAPK is implicated in the transmission of AMPA signaling to the nucleus and requires extracellular Ca2+, and PLC/PKC activation.
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PMID:Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors. 1009 77

The transcription factor NF-kappaB has been implicated in the synaptic plasticity and neurotoxicity mediated by ionotropic glutamate receptors in the striatum. However, the class of glutamate receptor and the intracellular pathways involved have not been determined. Kainate, but not AMPA or NMDA, was found to activate NF-kappaB in superfused slices of rat striatum. A similar activation was produced by the calcium ionophore A23187. The NF-kappaB activation by kainate was not observed in the absence of extracellular calcium, and was blocked by the p44/p42 MAP kinase inhibitor PD98059, but not by the p38 MAP kinase inhibitor SB203580. This demonstrates that striatal kainate receptors are coupled to NF-kappaB activation via calcium influx and p44/p42 MAP kinase activation.
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PMID:Kainate receptors activate NF-kappaB via MAP kinase in striatal neurones. 1067 93

In human and rodent macrophages, activation of the P2X7 nucleotide receptor stimulates interleukin-1beta processing and release, apoptosis, and killing of intracellular Mycobacterium tuberculosis. Signaling pathways downstream of this ionotropic ATP receptor are poorly understood. Here we describe the rapid activation of the stress-activated protein kinase (SAPK)/JNK pathway in BAC1 murine macrophages stimulated by extracellular ATP. Brief exposure of the cells to ATP (10-30 min) was sufficient to trigger a rapid accumulation of activated SAPK that was then sustained for >120 min. Several observations indicated that the P2X7 receptor mediated this effect. 1) ATP and 3'-O-(4-benzoyl)benzoyl-ATP were the only agonistic nucleotides. 2) The effect was inhibited by oxidized ATP and the isoquinoline KN-62, two known P2X7 receptor antagonists. 3) ATP-induced SAPK activation could be recapitulated in P2X7 receptor-transfected HEK293 cells, but not in wild-type HEK293 cells. Because P2X7 receptor stimulation can rapidly activate caspase family proteases that have been implicated in the induction of the SAPK pathway, we investigated whether ATP-dependent SAPK activation involved such proteases. Brief exposure of BAC1 macrophages to extracellular ATP induced DNA fragmentation, alpha-fodrin breakdown, and elevated levels of caspase-3-type activity. Asp-Glu-Val-Asp-cho, a caspase-3 inhibitor, inhibited ATP-induced DNA fragmentation and alpha-fodrin proteolysis, but had no effect on ATP-induced SAPK activation. Tyr-Val-Ala-Asp-chloromethyl ketone, a caspase-1 inhibitor, prevented ATP-induced release of processed interleukin-1beta, but not ATP-dependent SAPK activity. We conclude that activation of ionotropic P2X7 nucleotide receptors triggers a strong activation of SAPK via a pathway independent of caspase-1- or caspase-3-like proteases.
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PMID:Stress-activated protein kinase/JNK activation and apoptotic induction by the macrophage P2X7 nucleotide receptor. 1085 31

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the mammalian brain plays a central role in synaptic plasticity underlying refinement of neuronal connections during development, or processes like long-term potentiation (LTP), learning and memory. On the other hand, over-activation of glutamate receptors leading to neurodegeneration has been implicated in major areas of brain pathology. Any sustained effect of a transient NMDA receptor activation is likely to involve signaling to the nucleus and coordinated changes in gene expression. Classically, a set of immediate-early genes is induced first; some of them are themselves transcription factors that control expression of other target genes. This review deals with the induction of Fos, Jun and Egr (Krox) transcription factors in response to NMDA or non-NMDA (AMPA/kainate) ionotropic receptor agonists in vivo or in neuronal cultures in vitro. In addition, the mechanism of induction of a model immediate-early gene c-fos in response to Ca2+ influx through activated NMDA receptors or voltage-sensitive calcium channels is discussed. Both modes of calcium entry induce c-fos via activation of multiple signaling pathways that converge on constitutive transcription factors cAMP-response element-binding protein (CREB), serum response factor (SRF) and a ternary complex factor (TCF), such as Elk-1. In contrast to the traditional view of the NMDA receptor as a ligand-gated calcium channel, whose activation leads to calcium influx and activation of Ca2+/calmodulin-dependent kinases, recent evidence highlights involvement of the Ras/ mitogen-activated protein kinase (MAPK) pathway in the NMDA signaling to the nucleus.
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PMID:Molecular mechanisms associated with long-term consolidation of the NMDA signals. 1100 45

The members of the mitogen-activated protein (MAP) kinase family -- p44/p42 MAP kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAP kinase (p38) are known to be important mediators of the physiological plasticity or neurotoxicity induced in the striatum by activation of ionotropic glutamate receptors. However, our knowledge of the class of glutamate receptor and the intracellular pathways involved derives totally from studies on embryonic neurons, where the mechanisms are likely to be totally different from those operating in mature neurons. In superfused striatal slices from adult rats, NMDA and kainate, but not AMPA, were found to activate ERK. No activation of p38 or JNK was detected following treatment with any ionotropic glutamate receptor agonist. The activation of ERK by kainate was blocked by the ERK kinase (MEK) inhibitor PD98059, and the PI3 kinase inhibitor wortmannin, but not by the p38 MAP kinase inhibitor SB203580. This provides evidence for a novel pathway linking striatal kainate receptors to ERK activation via PI3 kinase and MEK.
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PMID:Activation of p44/p42 MAP kinase in striatal neurons via kainate receptors and PI3 kinase. 1131 83

The aim of this work was to investigate whether excitotoxicity induced by overstimulation of different ionotropic glutamate receptors could trigger different intracellular signaling cascades. Cultured chick neuronal retina cells, essentially amacrine-like, were particularly sensitive to the toxicity induced by non-NMDA glutamate receptor agonists. One hour stimulation with 100 microM kainate induced a reduction of cell viability of about 44%, as assessed by the MTT test 24 hr after stimulation. Kainate-induced toxicity was mediated through AMPA receptors. Glutamate (100 microM, 1 hr) reduced cell viability by 26%, essentially acting through N-methyl-D-aspartate receptors. Five hours after stimulation, neuronal retina cells had an apoptotic-like nuclear morphology. In retinal neurons, the excitotoxic stimulation, with either glutamate or kainate, induced a calcium-dependent enhancement of the DNA-binding activity of the activating protein-1 (AP-1) transcription factor, which was maximal 2 hr after stimulation. Glutamate induced a greater increase in the AP-1 DNA-binding activity than did kainate. Supershift assays using antibodies directed against different members of the Fos and Jun protein families showed that the AP-1 complex in retinal neurons includes proteins of the Fos family, namely, Fra-2, c-Jun, and Jun D. The DNA-binding activity of the nuclear factor-kappaB transcription factor was not significantly changed upon excitotoxic stimulation with any agonist. Stimulation of glutamate receptors with 100 microM kainate or 100 microM glutamate for 2 min was sufficient to induce the activation of the extracellular signal-regulated kinase (ERK). Inhibition of the ERK activation with the MEK inhibitors U 0126 and PD 98059 increased the toxicity induced by kainate but was without effect on the toxicity induced by glutamate. These results indicate that, although stimulation with both glutamate receptor agonists increased ERK phosphorylation, only kainate-induced ERK activation correlates with the activation of a survival signaling pathway. Our results suggest that, in chick embryo retinal neurons, the signaling pathways that mediate excitotoxic cell death and neuroprotection are stimulus specific.
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PMID:Differential postreceptor signaling events triggered by excitotoxic stimulation of different ionotropic glutamate receptors in retinal neurons. 1174 84

In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery. AMPA stimulation in hippocampal slice cultures caused the selective activation of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either component of the AMPA receptor--MAPK pathway potentiated cellular damage due to serum deprivation, suggesting that this pathway facilitates compensatory signals in response to injury. Correspondingly, positive modulation of AMPA receptors with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK activation and reduced the extent of synaptic and neuronal degeneration resulting from excitotoxic episodes. CX516 was neuroprotective when infused into slices either before or after the insult. The Ampakine derivative also elicited neuroprotection in an in vivo model of excitotoxicity as evidenced by reduction in lesion size and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK pathway selectively protects against excitotoxicity since enhancing the pathway did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal dysfunction. The results indicate that glutamatergic communication is important for cellular maintenance and that AMPA receptors activate survival signals to counterpoise their own excitotoxic potential.
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PMID:Survival signaling and selective neuroprotection through glutamatergic transmission. 1186 32


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