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:3.1.4.3 (phospholipase C)
18,461 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

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

The action of antidepressant drugs on monoamines such as norepinephrine and serotonin has been described for three decades. However, more-recent research has looked beyond cell surface receptors to transductional cascades and gene expression. Antidepressant drug therapies seem to share several mechanisms involved in either activating the adenylyl cyclase-protein kinase A cascade or inhibiting the phospholipase C-protein kinase C mechanisms. These effects, ultimately, combine to regulate the expression of target genes. Several specific genes are known to be activated or inhibited by antidepressant therapies. Steady-state levels of mRNA for glucocorticoid and mineralocorticoid receptors, brain-derived neurotrophic factor and its receptor trkB, and preproenkephalin are enhanced, whereas those for corticotropin-releasing hormone, c-fos,N-methyl-D-aspartate receptor subunits, and nerve-growth factor 1A are reduced. New molecular genetic methods for identifying differentially expressed genes will aid in the development of targets for wholly new generations of antidepressant drug therapies.
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PMID:Intracellular mechanisms of antidepressant drug action. 1103 41

NIH-3T3 cells stably transfected with TrkB, the receptor for brain-derived neurotrophic factor (BDNF), were used to study the effects of NO and peroxynitrite on TrkB. 3-Morpholinosydnonimine (SIN-1), a donor of NO and O2- which immediately react to form peroxynitrite, induced TrkB tyrosine phosphorylation in a dose-dependent relationship from 2 to 40 mM. TrkB phosphorylation by SIN-1 was blocked by superoxide dismutase, which converts O2 to H2O2 and prevents its reaction with NO to form peroxynitrite, and by K252a, an inhibitor of TrkB phosphorylation by BDNF. Treatment with NO or O2- alone did not activate TrkB. Treatment directly with 1-4 mM peroxynitrite resulted in a dose-dependent increase in tyrosine phosphorylation of TrkB. SIN-1 treatment induced tyrosine phosphorylation of phospholipase C-gamma1 (PLC-gamma1) and induced its binding with activated TrkB, similar to that seen with BDNF downstream signaling pathways. These studies demonstrate activation of TrkB through peroxynitrite.
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PMID:Nitric oxide activation of TrkB through peroxynitrite. 1109 25

The TrkA receptor is activated primarily by nerve growth factor (NGF), but it can also be activated by high concentrations of neurotrophin 3 (NT-3). The pan-neurotrophin receptor p75(NTR) strongly inhibits activation of TrkA by NT-3 but not by NGF. To examine the role of p75(NTR) in regulating the specificity of TrkA signaling, we expressed both receptors in Xenopus oocytes. Application of NGF or NT-3 to oocytes expressing TrkA alone resulted in efflux of (45)Ca(2+) by a phospholipase C-gamma-dependent pathway. Coexpression of p75(NTR) with TrkA inhibited (45)Ca(2+) efflux in response to NT-3 but not NGF. The inhibitory effect on NT-3 activation of TrkA increased with increasing expression of p75(NTR). Coexpression of a truncated p75(NTR) receptor lacking all but the first 9 amino acids of the cytoplasmic domain inhibited NT-3 stimulation of (45)Ca(2+) efflux, whereas coexpression of an epidermal growth factor receptor/p75(NTR) chimera (extracellular domain of epidermal growth factor receptor with transmembrane and cytoplasmic domains of p75(NTR)) did not inhibit NT-3 signaling through TrkA. These studies demonstrated that the extracellular domain of p75(NTR) was necessary to inhibit NT-3 signaling through TrkA. Remarkably, p75(NTR) binding to NT-3 was not required to prevent signaling through TrkA, since occupying p75(NTR) with brain-derived neurotrophic factor or anti-p75 antibody (REX) did not rescue the ability of NT-3 to activate (45)Ca(2+) efflux. These data suggested a physical association between TrkA and p75(NTR). Documenting this physical interaction, we showed that p75(NTR) and TrkA could be coimmunoprecipitated from Xenopus oocytes. Our results suggest that the interaction of these two receptors on the cell surface mediated the inhibition of NT-3-activated signaling through TrkA.
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PMID:The extracellular domain of p75NTR is necessary to inhibit neurotrophin-3 signaling through TrkA. 1115 Feb 91

Little is known about the signal transduction pathways of TRK family receptors in neuroblastoma (NB) cells. In this study, an NB cell line, designated MP-N-TS, was established from an adrenal tumor taken from a 2-year-old boy. This cell line expressed both TRK-A and TRK-B receptors, which is rare in a single NB cell line. Therefore, the MP-N-TS cell line was used to determine whether the signal transduction through these constitutive receptors is functional. Three neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4 / 5 (NT-4 / 5), induced tyrosine phosphorylation of panTRK, and BDNF and NT-4 / 5 induced tyrosine phosphorylation of TRK-B. Tyrosine phosphorylation of panTRK and / or TRK-B by the neurotrophins was inhibited in the presence of a tyrosine kinase inhibitor K252a. Tyrosine phosphorylation of Src homologous and collagen (Shc), extracellular signal-regulated kinase (ERK)-1 and ERK-2, and phospholipase C-gamma1 (PLC-gamma1) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a. Activation of Ras, detected as the GTP-bound form of Ras, was induced by the three neurotrophins. The neurotrophins did not modulate the expressions of TRK-A or TRK-B mRNA, but they did induce the expression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, whereas exogenous BDNF and NT-4 / 5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4 / 5 increased the number of viable cells, while NGF did not. Our results demonstrate that the signal transduction pathways through TRK-A and TRK-B in MP-N-TS cells are functional and similar, and the main downstream signaling pathways from the three neurotrophins are mitogen-activated protein kinase (MAPK) cascades through Shc, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-gamma1. Further, BDNF and NT-4 / 5 increased cell viability. The MP-N-TS cell line should be useful for clarifying the TRK-A and TRK-B signaling pathways responsible for the different prognoses in patients with NB.
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PMID:Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells. 1122 44

Recent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation during development but also in modulating synaptic strength in the mature brain. To understand how neurotrophins alter this synaptic modification, we have investigated the effect of brain-derived neurotrophic factor (BDNF) on long-term depression (LTD) at Schaffer collateral-CA1 synapses in rat hippocampal slices. The slices treated with BDNF for 5 min showed significantly less LTD in response to a 1-Hz tetanus compared with controls but displayed normal LTD when the afferents were tetanized at 10 Hz. Because BDNF enhanced long-term potentiation (LTP) induced by a 30-Hz tetanus, the synaptic modification threshold (theta(m)) as defined in the 'BCM' theory of Bienenstock Cooper & Monroe [Bienenstock et al. (1982), J. Neurosci., 2, 32-48] was not shifted. BNDF is likely to alter the capability of the plastic changes in synaptic efficacy, i.e. to produce an upward shift in the BCM curve. The suppressive effect of BDNF on LTD was prevented by either the tyrosine kinase (Trk) receptor inhibitor K252a or the phospholipase C inhibitor U73122. Thus, TrkB activation may attenuate LTD through phospholipase C signalling pathway.
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PMID:BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency-response curve of synaptic plasticity. 1215 39

During the development of the hippocampus, the action of GABA shifts from depolarizing to hyperpolarizing, and brain-derived neurotrophic factor (BDNF) has important roles in GABAergic transmission. We demonstrate that BDNF (20 ng ml-1) rapidly and reversibly potentiates postsynaptic GABAA receptor-mediated currents (by 80.5 +/- 14.3 %, n = 10) in hippocampal CA1 pyramidal neurons isolated from postnatal day (P)6 rats, using nystatin-perforated patch-clamp recordings. This potentiation is caused by an elevation of intracellular Ca2+ that occurs in response to the activation of Trk B receptor tyrosine kinase and phospholipase C-gamma. The modulation of the GABAA responses by BDNF in hippocampal CA1 pyramidal neurons isolated from P10 rats was more diverse (from potentiating to inhibitory), and at P14, BDNF induced a long-lasting inhibition. In addition, Ca2+/calmodulin-dependent protein kinase 2 plays important roles in the potentiating, but not in the inhibitory effect, of BDNF on the GABAA responses. These results suggest that changes in the intracellular signalling pathway could contribute to the developmental shift of the actions of BDNF on inhibitory systems.
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PMID:The action of BDNF on GABA(A) currents changes from potentiating to suppressing during maturation of rat hippocampal CA1 pyramidal neurons. 1264 7

The number of postsynaptic gamma-aminobutyric acid type A (GABAA) receptors is a fundamental determinant of the variability of inhibitory synaptic responses in the central nervous system. In rat visual cortex, [3H]SR-95531 binding assays revealed that brain-derived neurotrophic factor (BDNF), one of the neurotrophins, induced a rapid increase in the total number of cell surface GABAA receptors, through the activation of Trk B receptor tyrosine kinases. We also demonstrated that BDNF rapidly induced a sustained potentiation of GABAA receptor-mediated currents, using nystatin-perforated patch clamp recordings, in visual cortical layer 5 pyramidal neurons freshly isolated from P14 rats. The potentiation was caused by the activation of Trk B receptor tyrosine kinase and phospholipase C-gamma. In addition, intracellular Ca2+ was important for the potentiation of GABAA responses induced by BDNF. The selective increase in mean miniature inhibitory postsynaptic (mIPSC) current amplitude without effects on mIPSC time courses supports the idea that BDNF rapidly induces an increase in the total number of cell surface functional GABAA receptors in visual cortical pyramidal neurons. These results suggest that BDNF could alter the number of cell surface GABAA receptors in a region-specific manner.
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PMID:A rapid increase in the total number of cell surface functional GABAA receptors induced by brain-derived neurotrophic factor in rat visual cortex. 1294 63

A member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.
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PMID:Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. 1295 75


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