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)

Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the "epileptic receptors" (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the "GABA currents" (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant alpha1beta2gamma2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC.
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PMID:BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes. 1566 77

Neurotrophins exert many of their biological effects via the Trk receptor tyrosine kinases and require the regulated activation of distinct transcriptional and post-translational cellular events. Here we provide evidence for a novel signaling cascade from activated Trks to the transcription factor STAT5. Utilizing the STAT5 responsive element derived from the p21(WAF1/Cip1) promoter to modulate luciferase expression, neurotrophin-dependent activation of Trk A, B, and C was found to induce STAT5-mediated transcriptional response. Structure-function analysis using Trk A mutants in heterologous cells further revealed that the kinase activity and an intact phospholipase C-gamma binding site are required for STAT5 activation. In most cytokine responsive cell systems, STAT5 function is modulated by JAK2-dependent tyrosine phosphorylation. However, reconstitution studies using a JAK2 deficient cell line indicate that neurotrophin-induced STAT5 activation does not require the cognate upstream kinase JAK2. In contrast, the Src kinase inhibitor PP1 significantly abolishes STAT5-dependent transcription in Trk A expressing 293T cells and in BDNF-treated primary cortical neurons. Together these results suggest that neurotrophins may regulate neuronal gene expression via STAT5 in a JAK2 independent manner.
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PMID:Activation of STAT5-dependent transcription by the neurotrophin receptor Trk. 1570 76

Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits have been associated with a number of neuropsychiatric disorders, including schizophrenia. Differential PPI has been demonstrated also across various inbred mouse strains; however, the molecular mechanisms underlying these differences in sensorimotor gating remain unclear. Here, we sought to identify gene expression in the medial prefrontal cortex (mPFC) of mice associated with PPI using a laser microdissection and microarray analysis-based approach. C57BL/6 mouse substrains were used for the study as they have dramatically different PPI. Transcriptional analysis of closely related substrains was predicted to reduce the detection of genetic variation incidental to the phenotype. Microarray analysis comparing the mPFC of C57BL/6J to C57BL/6NHsd mice revealed neurotransmission- and cellular stress-related transcriptional responses associated with lower PPI. Down-regulation of metabotropic glutamate receptor 5, phospholipase C, and inositol monophosphatase 1 gene expression suggest altered phosphoinositide signaling, while decreased expression of a gamma-amino-butyric acid (GABA)A receptor subunit implies changes in GABAergic signaling. Genes involved in neuronal excitation and protection were also differentially expressed, including up-regulation of five immediate early genes and anti-apoptotic/survival factors as Bcl2-associated athanogene 3 and brain-derived neurotrophic factor. These data support previous findings of genetic influences on PPI, and provide novel insights into the molecular mechanisms regulating sensorimotor gating.
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PMID:Neurotransmission- and cellular stress-related gene expression associated with prepulse inhibition in mice. 1596 Nov 83

The effects of morphine on the gene expression of prepro-nociceptin/orphanin FQ (ppN/OFQ) in various primary cultured brain cells from embryonic day 17, rats were studied by use of real-time RT-PCR method. The basal level of ppN/OFQ mRNA in terms of ratio to the beta-actin in astrocytes was equivalent to that in neurons, but 10-times higher than that in microglia. The addition of 1 microM morphine significantly enhanced the ppN/OFQ mRNA levels in cultured astrocytes, but not neurons or microglia. The enhancement was observed as early as 1h after the addition of morphine, reached maximum at 6h. There was a concentration-dependency between 30 nM to 1 microM. The morphine-induced enhancement was abolished by naloxone, an antagonist of mu opioid peptide receptor (MOP), wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, and PD98059, a MEK inhibitor, but not by 1,10-phenanthroline, a metalloprotease inhibitor and U73122, a phospholipase C inhibitor. These profiles contrast to the data with morphine-induced enhancement of brain-derived growth factor (BDNF) gene expression in microglia, where 1,10-phenanthroline abolished the expression. Furthermore, the ELISA analysis revealed that the immunoreactive ppN/OFQ or N/OFQ level was also increased by morphine. The present findings suggest that astrocytes could play roles in the neuronal plasticity during morphine chronic treatments by enhancing gene expression of anti-opioid peptide, N/OFQ.
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PMID:Morphine-induced overexpression of prepro-nociceptin/orphanin FQ in cultured astrocytes. 1599 Jan 99

Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and recruitment of intracellular signaling molecules. The intracellular pathways used by neurotrophins share many common protein substrates that are used by other receptor tyrosine kinases (RTK), such as Shc, Grb2, FRS2, and phospholipase C-gamma. Here we describe a novel RTK mechanism that involves a 220-kilodalton membrane tetraspanning protein, ARMS/Kidins220, which is rapidly tyrosine phosphorylated in primary neurons after neurotrophin treatment. ARMS/Kidins220 undergoes multiple tyrosine phosphorylation events and also serine phosphorylation by protein kinase D. We have identified a single tyrosine (Tyr(1096)) phosphorylation event in ARMS/Kidins220 that plays a critical role in neurotrophin signaling. A reassembled complex of ARMS/Kidins220 and CrkL, an upstream component of the C3G-Rap1-MAP kinase cascade, is SH3-dependent. However, Tyr(1096) phosphorylation enables ARMS/Kidins220 to recruit CrkL through its SH2 domain, thereby freeing the CrkL SH3 domain to engage C3G for MAP kinase activation in a neurotrophin dependent manner. Accordingly, mutation of Tyr(1096) abolished CrkL interaction and sustained MAPK kinase activity, a response that is not normally observed in other RTKs. Therefore, Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors.
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PMID:Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation. 1628 1

Neurotrophins (NTs) induce gene transcription by binding their high-affinity tropomyosin-related kinase (Trk) receptors and initiating intracellular signal transduction cascades. In particular, activation of the cyclic AMP response element (CRE) in the promoters of target genes serves as surrogate markers for Trk receptor activation as demonstrated in both in vivo and in vitro systems. We used a HEK293 cell line stably expressing a CRE-luciferase reporter gene to develop an assay for monitoring Trk activation in response to their cognate ligands. Using TrkB, we showed that the assay was sensitive to physiological concentrations of brain-derived neurotrophic factor (BDNF) and that the signal was sufficiently robust to be suitable for implementation in high-throughput format. Further characterization of the TrkB expressing stable cell lines showed high-affinity binding for BDNF, a high density of receptor expression, and supported BDNF-mediated phosphorylation signaling. Consistent with this, inhibitors of phosphatidylinositol 3-kinase and the phospholipase C-gamma pathways led to reduction of BDNF-mediated luciferase responses. In contrast, inhibitors of mitogen-activated protein kinase pathways further potentiated BDNF responses. This assay was NT-Trk receptor pair-selective and shown to be further applicable to other Trk family members. This assay may be useful in screening compound libraries to identify Trk agonists, which may be applied towards discriminating between the activities of the different Trk receptor family members and the development of pharmacological drugs.
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PMID:Cyclic-AMP response element-based signaling assays for characterization of Trk family tyrosine kinases modulators. 1683 82

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
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PMID:Neurotrophin-regulated signalling pathways. 1693 74

Previous studies indicate that brain-derived neurotrophic factor (BDNF), through the mediation of the trkB receptor, modulates the expression of differentiated traits in basal forebrain (BF) oligodendrocytes (OLGs). Specifically, BDNF up-regulates the expression of myelin basic protein (MBP), proteolipid protein (PLP), and myelin associated glycoprotein (MAG; Du et al. [2006] Mol. Cell. Neurosci. 31:366-375). However, the signaling cascades mediating the effects of BDNF have not been defined. The current study employs biochemical and molecular biological approaches to examine the involvements of the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3 kinase (PI3K) pathway, and the phospholipase C-gamma (PLC-gamma) pathway. Our results indicate that, in BF OLGs, BDNF activates the MAPK pathway and the PLC-gamma pathway but not the PI3K-Akt signaling cascade. By using specific inhibitors and mutated dominant negative or constitutively active forms of MAPK kinase, we demonstrate that the MAPK pathway is mediating the effects of BDNF on expression of differentiated traits in BF OLGs.
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PMID:Mitogen-activated protein kinase pathway mediates effects of brain-derived neurotrophic factor on differentiation of basal forebrain oligodendrocytes. 1704 32

During the development of the rat hippocampus, both gamma-aminobutyric acid (GABA)(B) autoreceptors and brain-derived neurotrophic factor (BDNF) play important roles in the formation of GABAergic synapses as well as in the GABA(A) receptor-mediated transmissions. While a number of studies have reported rapid effects of BDNF on GABA(A) receptor-mediated responses, the interactions between GABA(B) autoreceptors and BDNF are less clear. Using conventional whole-cell patch-clamp recordings, we demonstrated here that BDNF significantly occludes baclofen-induced suppression of GABA(A) receptor-mediated transmissions in each of the preparations including hippocampal slices prepared from P14 rats, hippocampal CA1 pyramidal neurons isolated from P14 and P21 rats, and cultured hippocampal pyramidal neurons. This effect of BDNF was rapid and reversible, and was mediated via the activation of presynaptic TrkB receptor tyrosine kinases, and subsequent activation of phospholipase C and protein kinase C. On the contrary, in hippocampal CA1 pyramidal neurons isolated from P7 rats, BDNF failed to occlude the GABA(B) receptor-mediated inhibition of GABA release. Thus, the ability of BDNF to occlude the GABA(B) receptor-mediated inhibition of GABA release develops between P7 and P14. This demonstrates a novel aspect of the effects of BDNF on inhibitory transmissions in rat hippocampus, which may have some functional roles in the induction of developmental plasticity and/or pathophysiology of epilepsy.
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PMID:BDNF occludes GABA receptor-mediated inhibition of GABA release in rat hippocampal CA1 pyramidal neurons. 1707 39

Localization of Trk neurotrophin receptors is an important factor in directing cellular communication in developing and mature neurons. One potential site of action is in lipid raft membrane microdomains. Although Trk receptors have been localized to lipid rafts, little is known about how these neurotrophin receptors are directed there or how localization to these membrane microdomains regulates Trk signaling. Here, we report that the TrkB brain-derived neurotrophic factor (BDNF) receptor specifically localized to intracellular lipid rafts in cortical and hippocampal membranes in response to BDNF and that this process was critically dependent on the tyrosine kinase Fyn. BDNF-induced TrkB accumulation at lipid rafts was prevented by blocking the internalization of TrkB. BDNF stimulation also resulted in the association between endogenous TrkB and Fyn. Moreover, in neurons derived from Fyn knock-out mice, the translocation of TrkB to lipid rafts in response to BDNF was compromised, whereas the corticohippocampal region of Fyn mutants displayed lower amounts of TrkB in lipid rafts in vivo. In support of a role for lipid rafts in neurotrophin signaling, inhibiting TrkB translocation to lipid rafts, either by using Fyn knock-out neurons or lipid raft-disturbing agents, prevented the full activation of TrkB and of downstream phospholipase C-gamma. These results indicate that the lipid raft localization of TrkB receptors is regulated by Fyn and represents an important factor in determining the outcome of BDNF signaling in neurons.
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PMID:The tyrosine kinase Fyn determines the localization of TrkB receptors in lipid rafts. 1747 94


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