Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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)

The roles of Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) and mitogen-activated protein kinase (MAPK) in long-term potentiation (LTP) were investigated in the CA1 area of hippocampal slices, using electrophysiological and biochemical approaches. A brief high-frequency stimulation, but not low-frequency stimulation, delivered to Schaffer collateral/commissural afferents produced a stable LTP and activated both CaM kinase II and 42 kDa MAPK. Different from the activity of CaM kinase II, the increase in MAPK activity was transient. At a concentration of 50 microM, but not of 30 microM, PD098059, a potent inhibitor of MAPK kinase, markedly inhibited the induction of LTP. Although the two concentrations had similar inhibitory effects on MAPK activity, only 50 microM PD098059 suppressed the activation of CaM kinase II. Application of calmidazolium, an antagonist of calmodulin, blocked both CaM kinase II activation and the LTP induction without affecting the increase in 42 kDa MAPK activity. Application of neurotrophin brain-derived neurotrophic factor (BDNF) promoted the induction of LTP, with concomitant activation of CaM kinase II. Under the same conditions, BDNF failed to activate MAPK in hippocampal slices. These results indicate that, although the LTP induction is accompanied by increases in two kinase activities, only CaM kinase II activation is required for this event.
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PMID:Differential roles of Ca(2+)/calmodulin-dependent protein kinase II and mitogen-activated protein kinase activation in hippocampal long-term potentiation. 1049 30

These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the effect of three daily intra-ventral tegmental area (VTA) microinjections of neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the behavioral-activating effects of a subsequent challenge injection of cocaine in rats. Results indicated that, although NT-3 did not influence behavior across the three microinjection days, animals displayed a sensitized behavioral response to the subsequent cocaine challenge injection. In contrast, BDNF microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A second series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization to cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was microinjected into the VTA before three daily cocaine injections. Although PD98059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injections on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocampus were assessed. Results indicated that an acute cocaine injection resulted in a transient increase in NT-3 mRNA levels in the VTA. Collectively, these results suggest that NT-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progressive augmentation in behavioral activation with repeated administration.
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PMID:Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. 1049 69

Retinoic acid (RA) induces the differentiation of many cell lines, including those derived from neuroblastoma. RA treatment of SH-SY5Y cells induces the appearance of functional Trk B and Trk C receptors. Acute stimulation of RA-predifferentiated SH-SY5Y cells with brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), or neurotrophin 4/5 (NT-4/5), but not nerve growth factor (NGF), induces Trk autophosphorylation, followed by phosphorylation of Akt and the extracellular signal-regulated kinases (ERKs) 1 and 2. In addition, BDNF, NT-3, or NT-4/5, but not NGF, promotes cell survival and neurite outgrowth in serum-free medium. The mitogen-activated protein kinase and ERK kinase (MEK) inhibitor PD98059 blocks BDNF-induced neurite outgrowth and growth-associated protein-43 expression but has no effects on cell survival. On the other hand, the phosphatidylinositol 3-kinase inhibitor LY249002 reverses the survival response elicited by BDNF, leading to a cell death with morphological features of apoptosis.
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PMID:Extracellular-regulated kinases and phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor-mediated survival and neuritogenesis of the neuroblastoma cell line SH-SY5Y. 1050 Nov 84

Brain-derived neurotrophic factor contributes profoundly to modulate activity-dependent synaptic plasticity in adult brain areas such as the hippocampus, but the mechanisms underlying this important role still remain unclear. Recently, we have shown that two serine/threonine kinases, calcium/calmodulin-dependent protein kinase-2 and casein kinase-2, are capable of mediating brain-derived neurotrophic factor responses in adult rat hippocampus. In the present study, using hippocampal slices from adult rat, we show that phospholipase C-regulated calcium signals couple the brain-derived neurotrophic factor receptor to two distinct pathways: a pathway in which calcium/calmodulin-dependent protein kinase-2 stimulates a signalling module involving the p38 subfamily of mitogen-activated protein kinases and its downstream target, usually named mitogen-activated protein kinase-activated protein kinase-2; and a pathway in which the extracellular signal-regulated kinase subfamily of mitogen-activated protein kinases activates casein kinase-2. Our results suggest that: (i) extracellular signal-regulated kinase is activated by B-Raf in response to a calcium-sensitive adenylate cyclase; and (ii) extracellular signal-regulated kinase activates casein kinase-2 via a protein phosphatase(s) that may be of the PP1 and/or PP2A type. Interestingly, we also show that neurotrophin-induced activation of the two signalling cascades promotes a sustained activation of mitogen-activated protein kinase-activated protein kinase-2 and casein kinase-2 in slices. Considering the ability of these two kinases to be persistently activated, and that most of the protein kinases which lie in these pathways are believed to be important for multiple events underlying neuronal plasticity, it is suggested that the mechanisms described here might contribute both to rapid synaptic changes through local effects and to long-lasting synaptic responses through new gene transcription in the hippocampus.
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PMID:Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. 1067 Apr 37

Phosphorylation of the neurofilament-H subunit (NF-H) was investigated in rat embryonic brain neurons in culture. A portion of the NF-H was phosphorylated in vivo at embryonic day 17 when brain neurons were prepared. When the neurons were isolated and cultured, the NF proteins disappeared once and then reappeared over the next several days in the following order: (1) NF-L/NF-M, (2) dephosphorylated NF-H and (3) phosphorylated NF-H. Phosphorylation of NF-H began around 4 days after cell plating, at about the time of synapse formation. Treatments that appeared to modulate the timing of synapse formation also affected the timing of NF-H phosphorylation: (1) earlier phosphorylation was observed at higher neuronal cell density, (2) earlier phosphorylation was observed in neurons cultured on a coating substrate that promotes rapid neurite extension and (3) phosphorylation was suppressed when neurite extension was inhibited by brefeldin A. Three possible synapse formation-induced events, excitation, cell-cell contact through adhesion proteins and elevated concentrations of neurotrophic factors, were examined for their possible involvement in generating the signal for NF-H phosphorylation. Neither excitation nor cell contact enhanced NF-H phosphorylation. Neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) stimulated phosphorylation of NF-H. The BDNF-stimulated phosphorylation was inhibited by an anti-BDNF antibody and K252a, an inhibitor of BDNF receptor TrkB tyrosine kinase. Among known NF-H kinases of cyclin-dependent kinase 5 (CDK5), external signal-regulated protein kinase (ERK) and stress-activated protein kinase (SAPK), CDK5 and SAPK showed an increase in kinase activity or an active form with a time course similar to NF-H phosphorylation in control culture. On the other hand, BDNF stimulated the kinase activity of CDK5 and induced appearance of an active form of ERK transiently. These results suggest a possibility that synapse formation induces NF-H phosphorylation, at least in part, through activation of CDK5 by BDNF.
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PMID:Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons. 1068 53

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

We examined enhancement of synaptic transmission by neurotrophins at the presynaptic level. In a synaptosomal preparation, brain-derived neurotrophic factor (BDNF) increased mitogen-activated protein (MAP) kinase-dependent synapsin I phosphorylation and acutely facilitated evoked glutamate release. PD98059, used to inhibit MAP kinase activity, markedly decreased synapsin I phosphorylation and concomitantly reduced neurotransmitter release. The stimulation of glutamate release by BDNF was strongly attenuated in mice lacking synapsin I and/or synapsin II. These results indicate a causal link of synapsin phosphorylation via BDNF, TrkB receptors and MAP kinase with downstream facilitation of neurotransmitter release.
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PMID:Synapsins as mediators of BDNF-enhanced neurotransmitter release. 1072 20

Neurotrophins play a crucial role in the developmental plasticity of the visual cortex, but very little is known about the cellular mechanisms involved in their action. In many models of synaptic plasticity, increases in cytosolic calcium concentration and activation of the transcription factor cAMP response element-binding protein (CREB) are crucial factors for the induction and maintenance of long-lasting changes of synaptic efficacy. Whether BDNF modulates intracellular calcium levels in visual cortical neurons and the significance of this action for BDNF signal transduction is still controversial. We investigated whether CREB phosphorylation and calcium changes are elicited by acute BDNF presentation in postnatal visual cortical slices and cultures. We found that BDNF did not cause any calcium increase, but it induced robust CREB phosphorylation in neurons from both preparations. We further analyzed signal transduction and its dependency on calcium changes in cultured neurons. CREB phosphorylation required trkB activation because treatment with the trk inhibitor k252a completely blocked CREB phosphorylation. In agreement with the imaging experiments, we verified that calcium changes were not necessary for CREB activation because preincubation with BAPTA-AM did not diminish the level of CREB phosphorylation induced by BDNF stimulation. CREB phosphorylation was accompanied by gene expression, because we observed the upregulation of c-fos expression, which was also not affected by preincubation with BAPTA-AM. Finally, BDNF caused phosphorylation of mitogen-activated protein kinase (MAPK), and because the treatment with the MAPK inhibitor U0126 completely abolished CREB activation and c-fos upregulation, it is likely that both processes depend mainly on the MAP kinase pathway. These results indicate that MAPK and CREB, but not intracellular calcium, are important mediators of neurotrophin actions in the visual cortex.
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PMID:Brain-derived neurotrophic factor causes cAMP response element-binding protein phosphorylation in absence of calcium increases in slices and cultured neurons from rat visual cortex. 1075 32

Neurotrophins mediate their signals through two different receptors: the family of receptor tyrosine kinases, Trks, and the low affinity pan-neurotrophin receptor p75. Trk receptors show more restricted ligand specificity, whereas all neurotrophins are able to bind to p75. One important function of p75 is the enhancement of nerve growth factor signaling via TrkA by increasing TrkA tyrosine autophosphorylation. Here, we have examined the importance of p75 on TrkB- and TrkC-mediated neurotrophin signaling in an MG87 fibroblast cell line stably transfected with either p75 and TrkB or p75 and TrkC, as well as in PC12 cells stably transfected with TrkB. In contrast to TrkA signaling, p75 had a negative effect on TrkB tyrosine autophosphorylation in response to its cognate neurotrophins, brain-derived neurotrophic factor and neurotrophin 4/5. On the other hand, p75 had no effect on TrkB or TrkC activation in neurotrophin 3 treatment. p75 did not effect extracellular signal-regulated kinase 2 tyrosine phosphorylation in response to brain-derived neurotrophic factor, neurotrophin 3, or neurotrophin 4/5. These results suggest that the observed reduction in TrkB tyrosine autophosphorylation caused by p75 does not influence Ras/mitogen-activated protein kinase signaling pathway in neurotrophin treatments.
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PMID:p75 reduces TrkB tyrosine autophosphorylation in response to brain-derived neurotrophic factor and neurotrophin 4/5. 1082 63

This study reports that insulin-like growth factor I (IGF-I) prevents cerebellar granule cells from developing sensitivity to kainate neurotoxicity. Sensitivity to kainate neurotoxicity normally develops 5-6 days after switching cultures to a serum-free medium containing 25 mM K(+). Addition of either IGF-I or insulin to the serum-free medium at the time of the switch prevented the development of sensitivity to kainate, whereas brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and nerve growth factor did not. The dose-response curves indicated IGF-I was more potent than insulin, favoring the assignment of the former as the physiological protective agent. The phosphatidylinositol 3-kinase (PI 3-K) inhibitors wortmannin (10-100 nM) and LY 294002 (0.3-1 microM) abolished the protection afforded by IGF-I. The p70 S6 kinase (p70(S6k)) inhibitor rapamycin (5-50 nM:) also abolished the protection afforded by IGF-I. The activities of both enzymes decreased in cultures switched to serum-free medium but increased when IGF-I was included; wortmannin (100 nM) lowered the activity of PI 3-K from 2 to 5 days after medium switch, whereas rapamycin (50 nM) prevented the increase observed for p70(S6k) activity over the same interval. The mitogen-activated protein kinase kinase inhibitor U 0126 and the mitogen-activated protein kinase inhibitor SB 203580 did not abolish IGF-I protection. Kainate neurotoxicity was not prevented by Joro spider toxin; therefore, the development of kainate neurotoxicity could not be explained by the formation of calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. These results indicate that IGF-I functions through a signal transduction pathway involving PI 3-K and p70(S6k) to prevent the development of sensitivity to kainate neurotoxicity in cerebellar granule cells.
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PMID:Insulin-like growth factor I prevents the development of sensitivity to kainate neurotoxicity in cerebellar granule cells. 1098 35


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