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)

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

PGF2alpha triggers the demise of the corpus luteum whereby progesterone synthesis is inhibited, the luteal structure regresses, and the estrus cycle resumes. Upon binding to its heterotrimeric G-protein-coupled receptors, PGF2alpha initiates the phospholipase C/diacylglycerol and inositol-1,4,5-trisphosphate/Ca(2+)-protein kinase C (PKC) signaling pathway. More recently, we have demonstrated that PGF2alpha activates extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase signaling through a Raf-dependent mechanism in bovine luteal cells. However, the relationship between PKC and ERK activation in PGF2alpha signaling has not been clearly defined. Moreover, the signaling pathway that PGF2alpha uses to regulate gene expression is unknown. In this report, primary cultures of bovine luteal cells were used to address the role of PKC in ERK activation and the signaling pathway for induction of c-fos and c-jun messenger RNA (mRNA) expression in response to PGF2alpha. By using a PKC inhibitor and a PKC-deficient luteal cell model, we observed that phorbol ester-responsive isoforms of PKC were required for ERK phosphorylation and activation by PGF2alpha (1 microM) or phorbol 12-myristate 13-acetate (PMA) (20 nM). In PGF2alpha- and PMA-treated cells, active ERK MAP kinase was localized in the nucleus. PGF2alpha-induced ERK phosphorylation was dose-dependently inhibited by the MEK1 inhibitor PD098059 (1-50 microM). The expression of c-fos and c-jun mRNA in luteal cells was markedly increased by treatment with PGF2alpha (1 microM) or PMA (20 nM) for 30 min. We also observed that activation of ERK MAP kinase was required for the expression of c-fos and c-jun mRNA in response to PGF2alpha and PMA because it was abrogated by blocking the ERK pathway with PD098059. In addition, PGF2alpha and PMA-induced c-fos and c-jun mRNA expression was abolished in the PKC-deficient cells. Taken together, our data demonstrate that a PKC-dependent ERK MAP kinase pathway mediates the expression of c-fos and c-jun mRNA in PGF2alpha-treated bovine luteal cells.
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PMID:Induction of c-fos and c-jun messenger ribonucleic acid expression by prostaglandin F2alpha is mediated by a protein kinase C-dependent extracellular signal-regulated kinase mitogen-activated protein kinase pathway in bovine luteal cells. 1115 62

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

To explore the functional role of phospholipase C-gamma1 (PLC-gamma1) in the induction of immediate early genes (IEGs), we have examined the influence of Plcg1 gene disruption on the expression of 14 IEG mRNAs induced by platelet-derived growth factor (PDGF). Plcg1-null embryos were used to produce immortalized fibroblasts genetically deficient in PLC-gamma1 (Null cells), and retroviral infection of those cells was used to derive PLC-gamma1 re-expressing cells (Null+ cells). In terms of PDGF activation of PDGF receptor tyrosine phosphorylation as well as the mitogen-activated protein kinases Erk1 and Erk2, Null and Null+ cells responded equivalently. However, the PDGF-dependent expression of all IEG mRNAs was diminished in cells lacking PLC-gamma1. The expression of FIC, COX-2, KC, JE, and c-fos mRNAs were most strongly compromised, as the stimulation of these genes was reduced by more than 90% in cells lacking PLC-gamma1. The combination of PMA and ionomycin, downstream analogs of PLC activation, did provoke expression of mRNAs for these IEGs in the Null cells. We conclude that PLC-gamma1 is necessary for the maximal expression of many PDGF-induced IEGs and is essential for significant induction of at least five IEGs.
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PMID:Phospholipase C-gamma1 is required for the induction of immediate early genes by platelet-derived growth factor. 1125 53

Studies were undertaken to determine whether PTH-related protein (PTHrP) (107-139) mobilizes [Ca(2+)](i) in osteoblastic osteosarcoma UMR 106 cells. PTHrP (107-139), in a manner similar to PTHrP (107-111), induced a rapid [Ca(2+)](i) response in these cells that was dose dependent (EC(50) of approximately 0.1 pM) and more efficient than that of PTHrP (1-36) (EC(50) of approximately 1 nM). This effect of PTHrP (107-139) was abrogated by micromolar doses of verapamil or nifedipine. However, it was unaffected by 10 microM U73122 (a phospholipase C inhibitor), 100 microg/ml heparin (an inositol 1,4,5-trisphosphate receptor inhibitor), or 400 ng/ml pertussis toxin (a G(i) inhibitor), which inhibited the [Ca(2+)](i) response to PTHrP (1-36), or by either 25 nM bisindolylmaleimide I (BIM), a protein kinase (PK) C inhibitor, or 1 microM phorbol-12-myristate-13-acetate preincubation (22 h). PTHrP (107-139) and PTHrP (1-36), at 100 nM, desensitized the [Ca(2+)](i) response to a second challenge with the same peptide, but not with the other peptide in these cells. PTHrP (7-34), a type 1 PTH/PTHrP receptor (PTH1R) antagonist, decreased the effect of PTHrP (1-36) on [Ca(2+)](i). In contrast, PTHrP (107-111), but neither PTHrP (109-138) nor PTHrP (7-34), abolished this effect of PTHrP (107-139). Both PTHrP (107-139) and PTHrP (1-36), added together at submaximal doses, induced a higher [Ca(2+)](i) response. Moreover, PTHrP (107-139) increased the efficacy of PTHrP (1-36) on [Ca(2+)](i), but decreased its induced increase in PKA activity in these cells. Verapamil or nifedipine (at 50 microM) or 25 nM BIM, but not 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a PKA inhibitor, abolished the PTHrP (107-139)-induced increase in interleukin 6 messenger RNA (assessed by RT, followed by PCR) in UMR 106 cells. This peptide also increased c-fos messenger RNA in these cells; an effect inhibited by BIM, but unaffected by either verapamil or EGTA. These findings support the existence of high-affinity receptors for PTHrP (107-139), associated with an induced Ca(2+) influx, different from the PTH1R in UMR 106 cells. The present results suggest that PTHrP could affect bone turnover by interacting with the PTH1R and other yet unknown receptors in bone cells through complex mechanisms.
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PMID:C-terminal parathyroid hormone-related protein (PTHrP) (107-139) stimulates intracellular Ca(2+) through a receptor different from the type 1 PTH/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells. 1141 93

Arachidonic acid-derived mediators induce transcription of several immediate early genes, but the molecular mechanisms underlying these responses remain poorly characterized. We designed experiments to explore the mechanisms by which PGE(2) induces expression of transcription factor c-fos in glomerular mesangial cells. Binding of PGE(2) to prostaglandin receptors in mesangial cells stimulates both adenylate cyclase and phospholipase C-linked signaling pathways. Prostaglandin E(2) (PGE(2)) induced marked and transient accumulation of c-fos mRNA, but induction of the c-fos gene occurred independent of PGE(2)-stimulated adenylate cyclase activity. These results contrast with previous experiments in NIH 3T3 cells in which PGE(2) stimulated c-fos accumulation by a cAMP-dependent mechanism. We further showed that PGE(2) induces c-fos gene expression by increasing the transactivating capacity of the serum response element. Collectively, these results provide evidence of a cAMP-independent pathway linking PGE(2) receptors to transcriptional activation in the nucleus. Thus, activation of PGE(2) receptors in different cell types leads to both cAMP-independent and -dependent pathways for gene expression.
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PMID:Cyclic AMP-Independent Mechanisms of Nuclear Signal Transduction by PGE(2). 1185 8

Cd(2+) exposure increases the risk of cancer in humans and animals. In this report, we have studied the effect of Cd(2+) on signal transduction and Ca(2+) mobilization in murine macrophages. At micromolar concentrations, Cd(2+) significantly increased cell division as judged by [3H]thymidine uptake and cell counts. Cd(2+)-treated cells continued to proliferate even after more than 4 weeks in culture. Cd(2+) (1 microM) treatment induced a 1.5- to 2-fold increase in cytosolic free Ca(2+), [Ca(2+)](i), which was transitory and/or oscillatory. The sources of this Ca(2+) included both inositol 1,4,5-trisphosphate (IP(3))-sensitive and -insensitive stores. Macrophage treatment with 1-(6-((17beta-3-methoxyestra-1,2,5(10)-triene-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), decreased Cd(2+)-induced formation of IP(3) in a concentration-dependent manner (K(d) about 2 microM). This caused a concomitant, partial decrease in the effect of Cd(2+) on [Ca(2+)](i). Cd(2+) itself crosses the macrophage membrane in part via L-type Ca(2+) channels, but it also interacts with a cell surface membrane protein(s) coupled to a pertussis toxin-sensitive G protein. Use of selective inhibitors of signal transduction and the quantitation of the levels of phosphorylated MAPK/ERK-activating kinase-1 (MEK1), extracellular signal-regulated kinase-1 (ERK1), and p38 mitogen-activated protein kinase (MAPK) suggests that the effects of Cd(2+) are mediated by the p21(ras)-dependent MAPK, but not the phosphoinositide 3 (PI 3)-kinase signalling pathway. The effect of activating these pathways includes increased availability of the transcription factor NFkappaB as well as activation of the early genes c-fos and c-myc.
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PMID:Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. 1185 40

Glial cell line-derived neurotrophic factor (GDNF) has been recognized as a survival-promoting molecule for several neuronal populations in the central nervous system (CNS), including midbrain dopaminergic neurons and cortical neurons. Whereas it is well established that GDNF affects dopaminergic cell survival through a receptor complex composed of the tyrosine kinase, Ret, and the glycosylphosphatidylinositol (GPI)-anchored protein, GFRalpha-1, c-Ret is basically undetectable in cortical neurons. In the present study, we have compared GDNF signaling in cortical and mesencephalic neurons by using GDNF-induced expression of the immediate-early genes, c-fos and mgif, as a readout. We found that stimulation of embryonic day (E)17 cortical cultures for 3 hr with GDNF at concentrations ranging from 10 to 80 ng/ml did not result in detectable c-fos expression. In contrast, c-fos expression occurred in E14 mesencephalic cultures exposed to both low and high GDNF concentrations. Vice versa, cortical neurons responded to high GDNF concentrations (80 ng/ml) with an increase in mRNA encoding mGIF, while a similar mGIF response was absent in mesencephalic cultures. Cleavage of GFRalpha receptor subunits from their GPI anchors by phosphatidylinositol-specific phospholipase C (PIPLC) abolished GDNF-induced c-fos expression in mesencephalic cultures, but did not interfere with the effects of GDNF on cortical mgif expression. Together, these findings point to distinct differences in the GDNF recognition and/or signal transduction machinery of cortical and mesencephalic neurons.
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PMID:GDNF elicits distinct immediate-early gene responses in cultured cortical and mesencephalic neurons. 1254 3

Group I metabotropic glutamate receptors (mGluRs) are positively coupled to phospholipase C (PLC) via Galphaq-proteins and are expressed in the medium-sized projection neurons of striatum. To characterize the group I mGluR/PLC-sensitive modulation of intracellular Ca2+ ([Ca2+]i) signalling, primary neuronal cultures were prepared from the striatum of E19 rat embryos or neonatal day-1 rat pups. Cytoplasmic Ca2+ signals were examined with fura-2/AM at a signal cell level. After 17-18 days in culture, a profound Ca2+ response consisting of two phases was induced in cultured striatal neurons following bath application of the selective group I agonist, 3,5-dihydroxyphenylglycine (DHPG). The [Ca2+]i elevation was concentration- and time-dependent, and was blocked by coexposure to the group I antagonist, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), or the PLC inhibitor, U-73122, but not to the group II/III antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE). A series of further pharmacological studies demonstrated that the initial spike-like transient was dependent on intracellular Ca2+ mobilization through 1,4,5-triphosphate-sensitive stores, and the second long-lasting rise was dependent on extracellular Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors and especially L-type voltage-operated Ca2+ channels. Lastly, using an immediate early gene c-fos as a report of inducible gene expression, the resultant [Ca2+]i elevation contributes to DHPG-stimulated c-fos mRNA and Fos protein expression in striatal neurons as revealed by quantitative in situ hybridization and immunocytochemistry, respectively. These results demonstrate that group I mGluRs are able to affect Ca2+ homeostasis at multiple levels and trigger Ca2+-sensitive gene transcription in striatal neurons.
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PMID:Group I metabotropic glutamate receptor-mediated calcium signalling and immediate early gene expression in cultured rat striatal neurons. 1260 64

The Galphaq protein-coupled metabotropic glutamate receptor subtype-5 (mGluR5) is densely expressed in medium spiny projection neurons of striatum. Emerging evidence suggests a significant role of mGluR5 in the addictive plasticity of striatal neurons that is likely derived from inducible cellular gene expression related to stimulation of mGluR5 and associative signaling proteins. In this study, we found that activation of mGluR5 with a selective agonist (RS)-2-chloro-5-hydroxy-phenylglycine (CHPG) induced a rapid and transient phosphorylation of a transcription regulator Elk-1 in cultured striatal neurons from rat E19 embryos or neonatal day-1 pups. The Elk-1 phosphorylation was dose-dependent and occurred in neurochemically identified GABAergic neurons, but not glia. A series of experiments further demonstrated that the CHPG-stimulated Elk-1 phosphorylation was mediated through selective activation of mGluR5-regulated phospholipase C and associative second messenger system, i.e. 1,4,5,-triphosphate-sensitive Ca2+ release. Moreover, the Elk-1 phosphorylation was partially dependent on mGluR5-mediated co-activation of NMDA, but not kainate/AMPA receptors and L-type voltage-operated Ca2+ channels. Using an immediate early gene c-fos as a report of inducible gene expression, we found that CHPG induced marked c-fos mRNA expression. The c-fos induction kinetically corresponded to the Elk-1 phosphorylation and was attenuated by antisense oligonucleotides that selectively knocked down Elk-1 proteins. These results indicate that glutamatergic tone on mGluR5 is positively coupled to Elk-1 phosphorylation in striatal neurons via multiple signaling mechanisms involving Ca2+ release and NMDA activation, and the mGluR5-mediated Elk-1 phosphorylation facilitates gene transcription.
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PMID:Metabotropic glutamate receptor 5-regulated Elk-1 phosphorylation and immediate early gene expression in striatal neurons. 1271 32


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