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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-gamma (PLC-gamma) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-gamma. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-gamma, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.
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PMID:Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. 1049 6

Application of brain-derived neurotrophic factor (BDNF) to hippocampal neurons has profound effects on glutamatergic synaptic transmission. Both pre- and postsynaptic actions have been identified that depend on the age and type of preparation. To understand the nature of this diversity, we have begun to examine the mechanisms of BDNF action in cultured dissociated embryonic hippocampal neurons. Whole-cell patch-clamp recording during iontophoretic application of glutamate revealed that BDNF doubled the amplitude of induced inward current. Coexposure to BDNF and the NMDA receptor antagonist AP-5 markedly reduced, but did not entirely prevent, the increase in current. Coexposure to BDNF and ifenprodil, an NR2B subunit antagonist, reproduced the response observed with AP-5, suggesting BDNF primarily enhanced activity of NR2B-containing NMDA receptors with a lesser effect on non-NMDA receptors. Protein kinase involvement was confirmed with the broad spectrum inhibitor staurosporine, which prevented the response to BDNF. PKCI19-31 and H-89, selective antagonists of PKC and PKA, had no effect on the response to BDNF, whereas autocamtide-2-related inhibitory peptide, an antagonist of CaM kinase II, reduced response magnitude by 60%. These results demonstrate the predominant role of a specific NMDA receptor subtype in BDNF modulation of hippocampal synaptic transmission.
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PMID:Blockade of NR2B-containing NMDA receptors prevents BDNF enhancement of glutamatergic transmission in hippocampal neurons. 1049 7

The aim of the study was to determine which factors regulated the expression of neurotrophin-3 (NT-3) mRNA in cultured primary Schwann cells derived from sciatic nerve of neonatal rats. Treatment of primary Schwann cells with the adenylate cyclase activator, forskolin, or the cAMP agonist, 8-Br-cAMP, induced a significant reduction in NT-3 transcript levels. Transforming growth factor-beta1 (TGF-beta1) and glial growth factor 2 (GGF(2)) also reduced the levels of NT-3 mRNA in a dose and time-dependent manner. Treatment with nerve growth factor, brain-derived neurotrophic factor, NT-3, ciliary neurotrophic factor or interleukin-1beta was without effect. The TGF-beta1, GGF(2) and forskolin dependent reduction in NT-3 mRNA levels involved a destabilization of transcripts which was antagonised by co-treatment with cycloheximide. The cAMP-dependent protein kinase A (PKA) inhibitor, H-89, blocked the reduction in levels of NT-3 mRNA induced by TGF-beta1, GGF(2) and forskolin. The data show that the effects of TGF-beta1, GGF(2) and forskolin on the downregulation of NT-3 mRNA, at least in part, were due to a post-transcriptional event involving a labile protein intermediate under the control of PKA. The results suggest that the down-regulation of NT-3 mRNA in Schwann cells at a site of peripheral nerve damage may be mediated via a cAMP-dependent pathway and possibly involve neuroma-related elevations in TGF-beta1 and GGF(2).
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PMID:Transforming growth factor-beta1 and glial growth factor 2 reduce neurotrophin-3 mRNA expression in cultured Schwann cells via a cAMP-dependent pathway. 1052 80

Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons. They are also essential for modulating activity-dependent neuronal plasticity. Here we show that neurotrophins elicit action potentials in central neurons. Even at low concentrations, brain-derived neurotrophic factor (BDNF) excited neurons in the hippocampus, cortex and cerebellum. We found that BDNF and neurotrophin-4/5 depolarized neurons just as rapidly as the neurotransmitter glutamate, even at a more than thousand-fold lower concentration. Neurotrophin-3 produced much smaller responses, and nerve growth factor was ineffective. The neurotrophin-induced depolarization resulted from the activation of a sodium ion conductance which was reversibly blocked by K-252a, a protein kinase blocker which prefers tyrosine kinase Trk receptors. Our results demonstrate a very rapid excitatory action of neurotrophins, placing them among the most potent endogenous neuro-excitants in the mammalian central nervous system described so far.
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PMID:Neurotrophin-evoked rapid excitation through TrkB receptors. 1055 98

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

We have reported that the delta3 isoform of Ca2+/ calmodulin-dependent protein kinase II (CaM kinase II) is abundant in the nucleus in cerebellar granule cells. To examine the possibility that the nuclear isoforms of CaM kinase II are involved in the expression of brain-derived neurotrophic factor (BDNF), we transiently overexpressed the delta3 isoform in NG108-15 cells. The quantitative RT-PCR analysis revealed that rat cerebellum and NG108-15 cells expressed the exon IV-containing mRNA of BDNF (exon IV-BDNF mRNA) more than the exon III-BDNF mRNA. Treatment of NG108-15 cells with Bay K 8644 increased both exon III- and exon IV-BDNF mRNAs, and overexpression of the 83 isoform potentiated the expression of the exon IV-BDNF mRNA. The potentiation was not observed in the cells that were overexpressed with either the 61 isoform, a nonnuclear isoform, or the inactive mutant of the delta3 isoform. We constructed the luciferase reporter gene following the promoter upstream of exon IV and confirmed that overexpression of the delta3 isoform increased luciferase gene expression. Double-immunostaining of NG108-15 cells with the antibodies to CaM kinase II and BDNF clearly showed that BDNF was highly expressed in the cells that were overexpressed with the delta3 isoform or the alphaB isoform, another nuclear isoform of CaM kinase II. These results suggest that the nuclear isoforms of CaM kinase II are involved in the expression of BDNF.
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PMID:Increase of brain-derived neurotrophic factor gene expression in NG108-15 cells by the nuclear isoforms of Ca2+/ calmodulin-dependent protein kinase II. 1080 Sep 34

Serotonergic neurons in the central nervous system are crucial in the control of autonomic functions and behavior. Mechanisms by which development and maintenance of the serotonergic transmitter phenotype is regulated include activation of protein kinase A (PKA). Using cultures established from the E14 rat raphe we show here that forskolin (10 microM) increases numbers of neurons expressing tryptophan hydroxylase (TpOH), the key enzyme of serotonin synthesis, and uptake of the false serotonergic transmitter 5, 7-dihydroxytryptamine (5,7-DHT). As shown by short-term treatments the effect is due to phenotype induction rather than survival. To begin to understand downstream or parallel signaling pathways required for the PKA-mediated induction of serotonergic markers, we have studied the putative implication of brain-derived neurotrophic factor (BDNF) and its receptor trkB. Treatment of raphe neurons with forskolin induced BDNF mRNA assayed by competitive RT-PCR. Moreover, trkB-IgG receptor bodies fully prevented the forskolin-induced numerical increase in TpOH- and 5,7-DHT-positive cells suggesting an implication of a TrkB-activated pathway. TrkC-IgG had no effect. K252b, a specific inhibitor of trk kinase activity likewise abolished the induction of serotonergic markers by forskolin. In turn, the inductive effect of BDNF on serotonergic markers was blocked by KT5720, a specific inhibitor of PKA. Taken together, these data suggest that co-activation of cAMP- and trkB-dependent signaling pathways plays a crucial role in the regulation of the serotonergic neuronal phenotype.
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PMID:Brain-derived neurotrophic factor and trkB are essential for cAMP-mediated induction of the serotonergic neuronal phenotype. 1090 76

Althoughthe neurotrophins BDNF and NT-3 have been recognized as potent survival factors for distinct neuronal populations in the peripheral nervous system, they seem to have only minor effects on the survival of CNS neurons. In the present study, we provide evidence that BDNF and NT-3 require distinct additional extracellular signals in order to effectively promote the survival of several established populations of target neurons in the CNS. In dissociated cell cultures of the embryonic rat mesencephalon, BDNF promoted dopaminergic cell survival only after a delay of several days. Even after prolonged cultivation, survival promoting effects were completely absent with NT-3. Irrespective of the cultivation time, survival promoting effects of both BDNF and NT-3 on dopaminergic neurons were induced or potentiated upon simultaneous depolarization of cultured mesencephalic cells with NMDA or upon activation of cAMP/PKA-dependent signaling pathways with dibutyryl cAMP. Dibutyryl cAMP (dbcAMP), but not NMDA, also potentiated or induced the survival promoting effects of BDNF and NT-3 on cultured cerebellar granule cells. None of these substances, either alone or in combination, affected the survival of cultured cortical neurons. However, cortical cell survival increased upon depolarization with elevated potassium; an effect known to involve the induction of an autocrine BDNF loop. In both cerebellar and mesencephalic neurons, but not in cortical neurons, dbcAMP also potentiated neurotrophin-induced c-fos response, indicating intimate cross-coupling of signaling pathways activated by these different factors. Together these findings suggest that in the CNS, neurotrophins preferentially promote the survival of functionally active neurons. Our findings further reveal that the neuronal response to neurotrophins is modulated in a brain region-specific manner.
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PMID:Neurotrophins require distinct extracellular signals to promote the survival of CNS neurons in vitro. 1096 91

In this study, we explored whether a serotonergic (5-HT) phenotype could be novelly induced in the phenotypically plastic neurons of the developing striatum. We found that the 5-HT biosynthetic enzyme tryptophan hydroxylase (TPH) was expressed in nearly 10% of neurons following treatment with an extract derived from adult raphe tissue. This effect was mimicked by co-treatment with a growth factor (aFGF, bFGF or BDNF; but not GDNF, IGF-1, EGF or TGF) and the neurotransmitter 5-HT (but not GABA, dopamine, glutamate) and/or a protein kinase activator (IBMX, forskolin, TPA). Treatment with combined factors (aFGF+5-HT+IBMX+forskolin+TPA) yielded the greatest level of TPH induction (15.6%). Moreover, TPH was enzymatically active (112.8+/-36 pmol/mg per h) and produced detectable levels of 5-HT (2.12+/-0.30 ng) and its metabolite 5-HIAA (4.24+/-0.11 ng) in maximally stimulated cultures. These findings demonstrate that it is possible to promote the differentiation of serotonergic phenotypic traits in developing brain neurons in culture.
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PMID:Mechanisms governing the differentiation of a serotonergic phenotype in culture. 1098 Feb 41


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