Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of trophic factor receptors stimulates tyrosine phosphorylation on proteins and supports neuronal survival. We report that in the recovery phase following reversible cerebral ischemia, tyrosine phosphorylation increases in the membrane fraction of the resistant hippocampal CA3/dentate gyrus (DG) region, whereas in the sensitive CA1 region or striatum, tyrosine phosphorylation is less marked or decreases. In the cytosolic fractions, a 42-kDa protein, identified as mitogen-activated protein (MAP) kinase, is markedly phosphorylated and activated immediately following ischemia, in particular in CA3/DG, but not in striatum. In the CA1 region, phosphorylation of MAP kinase is less intense and decreases later during reperfusion, which could explain the delay of neuronal degeneration in this structure. The data suggest that in ischemia-resistant neurons the growth factor receptor-coupled signaling cascade is stimulated and, through its effects on DNA transcription and mRNA translation, supports neuronal survival.
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PMID:Tyrosine phosphorylation and activation of mitogen-activated protein kinase in the rat brain following transient cerebral ischemia. 751 Jul 79

Neurotransmitters and growth factors can trigger activation of a newly described family of mitogen-activated protein kinases. To help define the role of this kinase family in signal transduction in the nervous system, we have conducted immunohistochemical studies to localize p42 mitogen-activated protein kinase in rat brain sections. Light-microscopic studies revealed staining in neuronal cell bodies and dendrites that is particularly prominent in superficial layers of the neocortex, the hippocampal CA3 region and dentate gyrus, as well as cerebellar Purkinje cells. Discrete staining of oligodendrocytes was also apparent in fiber tracts, indicating expression of p42 mitogen-activated protein kinase in both neuronal and glial cell types. Electron-microscopic studies demonstrated that staining in dendrites is closely associated with microtubules. In the cell bodies, prominent staining was associated with the Golgi apparatus. In contrast, immunolabeling of synaptic terminals was not detected. Previous studies have demonstrated that p42 mitogen-activated protein kinase responds to neuronal stimulation. Immunohistochemical studies presented in this paper demonstrate prominent staining for this kinase in neuronal cell bodies and dendrites. Therefore, this kinase is likely to play a key role in postsynaptic signal transduction. As both p42 mitogen-activated protein kinase and microtubule-associated protein 2, an in vitro substrate of p42 mitogen-activated kinase, are associated with dendritic microtubules, this kinase may mediate effects of growth factors or neurotransmitters on the dendritic cytoskeleton.
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PMID:p42 mitogen-activated protein kinase in brain: prominent localization in neuronal cell bodies and dendrites. 837 38

MKP-1 (also known as CL100, 3CH134, Erp, and hVH-1) exemplifies a class of dual-specificity phosphatase able to reverse the activation of mitogen-activated protein (MAP) kinase family members by dephosphorylating critical tyrosine and threonine residues. We now report the cloning of MKP-3, a novel protein phosphatase that also suppresses MAP kinase activation state. The deduced amino acid sequence of MKP-3 is 36% identical to MKP-1 and contains the characteristic extended active-site sequence motif VXVHCXXGXSRSXTXXXAYLM (where X is any amino acid) as well as two N-terminal CH2 domains displaying homology to the cell cycle regulator Cdc25 phosphatase. When expressed in COS-7 cells, MKP-3 blocks both the phosphorylation and enzymatic activation of ERK2 by mitogens. Northern analysis reveals a single mRNA species of 2.7 kilobases with an expression pattern distinct from other dual-specificity phosphatases. MKP-3 is expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis. In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus. Metrazole-stimulated seizure activity triggers rapid (<1 h) but transient up-regulation of MKP-3 mRNA in the cortex, piriform cortex, and some amygdala nuclei. Metrazole stimulated similar regional up-regulation of MKP-1, although this was additionally induced within the thalamus. MKP-3 mRNA also undergoes powerful induction in PC12 cells after 3 h of nerve growth factor treatment. This response appears specific insofar as epidermal growth factor and dibutyryl cyclic AMP fail to induce significant MKP-3 expression. Subcellular localization of epitope-tagged MKP-3 in sympathetic neurons reveals expression in the cytosol with exclusion from the nucleus. Together, these observations indicate that MKP-3 is a novel dual-specificity phosphatase that displays a distinct tissue distribution, subcellular localization, and regulated expression, suggesting a unique function in controlling MAP kinase family members. Identification of a second partial cDNA clone (MKP-X) encoding the C-terminal 280 amino acids of an additional phosphatase that is 76% identical to MKP-3 suggests the existence of a distinct structurally homologous subfamily of MAP kinase phosphatases.
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PMID:MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. 862 80

The regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42(mapk)). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
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PMID:Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. 973 50

We investigated the expression, activation, and distribution of c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinases (p38s) and extracellular signal-regulated kinases (ERKs) using Western blotting and immunohistochemistry in gerbil hippocampus after transient forebrain ischemia to clarify the role of these kinases in delayed neuronal death (DND) in the CA1 subfield. Immunoblot analysis demonstrated that activities of JNK, p38, and ERK in whole hippocampus were increased after 5 min of global ischemia. We used an immunohistochemical study to elucidate the temporal and spatial expression of these kinases after transient global ischemia. The immunohistochemical study showed that active JNK and p38 immunoreactivities were enhanced at 15 min of reperfusion and then gradually reduced and disappeared in the hippocampal CA1 region. On the other hand, in CA3 neurons, active JNK and p38 immunoreactivities were enhanced at 15 min of reperfusion and peaked at 6 hr of reperfusion and then gradually reduced but was continuously detected 72 hr after ischemia. Active ERK immunoreactivity was observed transiently in CA3 fibers and dentate gyrus. Pretreatment with SB203580, a p38 inhibitor, but not with PD98059, an ERK kinase 1/2 inhibitor, reduced ischemic cell death in the CA1 region after transient global ischemia by inhibiting the activity of p38. These findings indicate that the p38 pathway may play an important role in DND during brain ischemia in gerbil. Components of the pathway are important target molecules for clarifying the mechanism of neuronal death.
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PMID:Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. 1084 20

Although the function of the p42/p44 mitogen-activated protein (MAP) kinase pathway in long-term potentiation at hippocampal CA3-CA1 synapses has been well described, relatively little is known about the importance of the p38 MAP kinase pathway in synaptic plasticity. Here we show that the p38 MAP kinase pathway, a parallel signaling cascade activated by distinct upstream kinases, mediates the induction of metabotropic glutamate receptor-dependent long-term depression at CA3-CA1 synapses. Thus, two parallel MAP kinase pathways contribute to opposing forms of long-term plasticity at a central synapse.
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PMID:Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. 1103 67

Brain-derived neurotrophic factor (BDNF) is implicated in long-term synaptic plasticity in the adult hippocampus, but the cellular mechanisms are little understood. Here we used intrahippocampal microinfusion of BDNF to trigger long-term potentiation (BDNF-LTP) at medial perforant path--granule cell synapses in vivo. BDNF infusion led to rapid phosphorylation of the mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated protein kinase) and p38 but not JNK (c-Jun N-terminal protein kinase). These effects were restricted to the infused dentate gyrus; no changes were observed in microdissected CA3 and CA1 regions. Local infusion of MEK (MAP kinase kinase) inhibitors (PD98059 and U0126) during BDNF delivery abolished BDNF-LTP and the associated ERK activation. Application of MEK inhibitor during established BDNF-LTP had no effect. Activation of MEK-ERK is therefore required for the induction, but not the maintenance, of BDNF-LTP. BDNF-LTP was further coupled to ERK-dependent phosphorylation of the transcription factor cAMP response element-binding protein. Finally, we investigated the expression of two immediate early genes, activity-regulated cytoskeleton-associated protein (Arc) and Zif268, both of which are required for generation of late, mRNA synthesis-dependent LTP. BDNF infusion resulted in selective upregulation of mRNA and protein for Arc. In situ hybridization showed that Arc transcripts are rapidly and extensively delivered to granule cell dendrites. U0126 blocked Arc upregulation in parallel with BDNF-LTP. The results support a model in which BDNF triggers long-lasting synaptic strengthening through MEK-ERK and selective induction of the dendritic mRNA species Arc.
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PMID:Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. 1188 Apr 83

gamma-Hydroxybutyrate (GHB) naturally occurs in the brain, but its exogenous administration induces profound effects on the central nervous system in animals and humans. The intracellular signaling mechanisms underlying its actions remain unclear. In the present study, the effects of GHB on the activation (phosphorylation) of mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase 1 and 2 (ERK1/2), were investigated. Acute administration of GHB (500 mg/kg, intraperitoneal) induced a fast and long lasting inhibition of MAP kinase phosphorylation in both frontal cortex and hippocampus. The reduced MAP kinase phosphorylation was observed in the CA1 and CA3 areas but not in the dentate gyrus. Pretreatment with the specific gamma-aminobutyric acid, type B (GABAB), receptor antagonist CGP56999A (20 mg/kg, intraperitoneal) prevented the action of GHB, and the effect of GHB was mimicked by baclofen, a selective GABAB receptor agonist, whereas the high affinity GHB receptor antagonist NCS-382 (200 mg/kg, intraperitoneal) had no effect on GHB-inhibited MAP kinase phosphorylation. Moreover, the GHB dehydrogenase inhibitor valproate (500 mg/kg, intraperitoneal), which inhibits the conversion of GHB into GABA, failed to block the effect of GHB on MAP kinase phosphorylation. Altogether, these data suggest that GHB, administered in vivo, reduces MAP kinase phosphorylation via a direct activation of GABAB receptors by GHB. In contrast, GHB (10 mm for 15 min) was found ineffective on MAP kinase phosphorylation in brain slices, indicating important differences in the conditions required for the second messenger activating action of GHB.
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PMID:Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus. 1292 92

The mitogen-activated protein (MAP) kinase cascades regulate a variety of cellular activities, including cell growth, proliferation, and apoptosis, and are reported to play a role in the actions of antidepressant treatment. There are a number of different classes of protein phosphatases that could influence the MAP kinase cascade. One of these, the MAP kinase phosphatase (MKP) family, is known to play a key role in dephosphorylation of activated MAP kinase. In the present study, we analyzed the expression of the MKP1, MKP2, and MKP3 isoforms in rat brain after electroconvulsive seizure (ECS), considered the most effective treatment for depression. In situ hybridization analysis demonstrates that ECS differentially regulates the expression of the MKP isoforms. Expression of MKP1 mRNA is robustly increased by acute ECS in the major cell layers of the hippocampus, including the dentate gyrus granule cell layer and the CA1 and CA3 pyramidal cell layers. In contrast, MKP2 is induced mainly in the dentate gyrus and MKP3 is preferentially increased in the CA1 and CA3 cell layers. In the prefrontal cortex, all three MKP isoforms are upregulated by acute ECS administration. Chronic ECS resulted in a similar pattern of induction for each of the MKP subtypes, demonstrating that there is little or no desensitization of the response to repeated ECS. The induction of MKP expression serves as negative feedback control for the MAP kinase cascades. Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment.
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PMID:Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain. 1549 35

Extracellular signal-regulated kinase 5 (ERK5), the newest member of the mitogen-activated protein (MAP) kinase family of proteins, is widely expressed in many tissues, including the brain. Here we investigated the activation and subcellular localization of ERK5 by immunoblotting and immunohistochemistry as well as its potential role following cerebral ischemia in rat hippocampus. Transient cerebral ischemia was induced by the four-vessel occlusion method in Sprague-Dawley rats. Our results first indicated that the strongly activated ERK5 immunoreactivity was seen in the CA3/DG region but not in the CA1 pyramidal cell of rat hippocampus following reperfusion. In cytosol extracts, ERK5 activation was rapidly increased, with a peak at 30 min, and then gradually decreased to basal level at 3 days of reperfusion. In nucleus extracts, both phospho-ERK5 and its protein expression were persistently enhanced during the later reperfusion period (from 6 hr to 3 days). To elucidate further the possible role of ERK5 activation and subcellular localization in ischemic insult, rats were intraperitoneally administrated with nifedipine (ND) and dextromethorphan (DM), inhibitors of two types of calcium channels, 20 min prior to ischemia. Our findings showed that ND or DM significantly reduced activated ERK5 immunoreactivity in the nucleus and that most of the CA3/DG neurons were lost 3 days later. Most importantly, intracerebroventricular infusion of ERK5 antisense oligonucleotides (AS; every 24 hr for 3 days before ischemia), but not sense oligonucleotides or vehicle, not only markedly decreased the level of ERK5 and p-ERK5 but also largely caused neuronal loss in the CA3/DG region at 3 days of reperfusion. Taken together, the results strongly suggest that ERK5 was selectively activated in the hippocampal CA3/DG region and subsequently translocated from the cytosol to the nucleus through activation of N-methyl-D-aspartate receptor and L-type voltage-gated calcium channel, which might act as an important survival signal in ischemia-induced neuronal cell damage of the CA3/DG region.
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PMID:Activation of extracellular signal-regulated kinase 5 may play a neuroprotective role in hippocampal CA3/DG region after cerebral ischemia. 1578 69


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