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)

Inflammatory processes occur in the central nervous system (CNS) through mechanisms that differ from other inflammation, and with distinct cellular effects. Neuronal injury in bacterial meningitis is not a monocausal event, but is mediated by several factors. One is possible direct toxicity of bacterial compounds. Lipoteichoic acid (LTA) is a cell wall component unique to Gram-positive bacteria. In a previous report, LTA could interact with CD14 to induce NF-kappaB activation, which is involved in transcriptional regulation of adhesion molecules, enzymes and cytokines. Although there are many aspects to neuroinflammation, the pathways involving the cyclooxygenase (COX)-2 and subsequent generation of prostaglandin clearly play a role. LTA has been shown to stimulate inflammatory responses in a number of in vivo and in vitro experimental models. However, little was known about the molecular mechanisms of LTA implicated in inflammatory responses in neurons. In this study, we characterized the mechanisms underlying signaling transduction in rat cortical neuronal cells challenged by LTA. Here, we first showed that in rat cortical neuronal cells, LTA might activate protein tyrosine kinase (PTK), phosphatidylcholine-specific phospholipase C (PC-PLC), and phosphatidylinositol-specific phospholipase C (PI-PLC) to induce protein kinase Cepsilon activation, which in turn induces extracellular signal-regulated kinase (ERK) activation, finally inducing PGE(2) release and COX-2 synthesis.
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PMID:Lipoteichoic acid induces prostaglandin E(2) release and cyclooxygenase-2 synthesis in rat cortical neuronal cells: involvement of PKCepsilon and ERK activation. 1646 74

The impact of the catecholamine epinephrine and the postulated inhibitory second messenger prostaglandin E(2) (PGE(2)) on the kinetics and magnitude of glucose-induced insulin secretion were compared and contrasted. In agreement with a number of studies, epinephrine was a most effective antagonist of glucose-induced insulin secretion. Dose-response studies using 8 to 10 mmol/L glucose as stimulant established that levels as low as 1 to 10 nmol/L of the catecholamine were effective at inhibiting release. Glucose (20 mmol/L) caused an approximately 25-fold increase in insulin secretion, an effect that was completely abolished by 1 micromol/L epinephrine. Under conditions where it completely abolished 20 mmol/L glucose-induced insulin release, epinephrine (1 micromol/L) reduced, but did not abolish, the stimulatory effect of glucose on phospholipase C activation. Chronic 3-hour exposure to 10 mmol/L glucose alone desensitized the islet to subsequent stimulation by glucose. Despite its ability to completely suppress secretion to 10 mmol/L glucose, epinephrine failed to protect the islet from hyperglycemia-induced desensitization. In sharp contrast to epinephrine, PGE(2) at levels ranging from 1 to 10 micromol/L had no discernible adverse effect on 10 mmol/L glucose-induced secretion. These findings suggest that multiple mechanisms contribute to the inhibitory impact of epinephrine on release and, in conjunction with other studies, cast serious doubt on the concept that PGE(2) plays any significant inhibitory role in the regulation of glucose-induced secretion.
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PMID:Divergent effects of epinephrine and prostaglandin E2 on glucose-induced insulin secretion from perifused rat islets. 1716 Dec 20

Prostaglandins are potent products of arachidonic acid metabolism that play significant roles in regulating ion transport in the kidney. In the Madin Darby canine kidney (MDCK) cell line prostaglandin E(1) (PGE(1)) stimulates the activity of the Na,K-ATPase and regulates transcription. Transient transfection studies conducted in MDCK cells with a human Na,K-ATPase beta1 subunit promoter/luciferase construct, pHbeta1-1141 Luc, showed a PGE(1) stimulation. The PGE(1) stimulation was inhibited by the PGE receptor antagonists SC19220 and AH6809, indicating the involvement of EP1 receptors (coupled to phospholipase C) and EP2 receptors (coupled to adenylate cyclase), respectively. A prostaglandin-regulatory element (PGRE) within the beta1 subunit promoter (-110 to -92, AGTCCCTGC) is sufficient to elicit a PGE(1) stimulation in a heterologous promoter (in pLUC-MCS). Studies with promoter mutants indicated that in addition to the PGRE, an adjacent Sp1 site was also essential for regulation by PGE(1). Consistent with the involvement of Sp1 are the results of DNA affinity precipitation studies, which indicate that Sp1 as well as CREB, and Sp3 all bind to the PGRE. The involvement of this PGRE in transcriptional regulation of the Na,K-ATPase beta1 gene was examined in a number of species. Only human and chimpanzee promoters possessed an identical PGRE site, unlike dog, rat, and mouse, which possessed Sp1 sites in similar locations. Two alternative PGREs were subsequently identified. The sequence of the one of these PGREs (TGACCTTC, -445 to -438) was conserved throughout all species examined, suggesting its physiologic significance.
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PMID:Prostaglandins regulate transcription by means of prostaglandin response elements located in the promoters of mammalian Na,K-ATPase beta 1 subunit genes. 1734 18

Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the micro-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[(35)S]thio)-triphosphate (GTPgamma[(35)S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTPgamma[(35)S] binding and inhibited both prostaglandin E(2) (PGE(2))-stimulated adenylyl cyclase activity and BK/PGE(2)-stimulated neuropeptide release. The effect of BK was blocked by the B(2) antagonist HOE 140 [D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin], but not by the B(1) antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH(2), and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of micro-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that micro-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of phospholipase C-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.
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PMID:Rapid modulation of micro-opioid receptor signaling in primary sensory neurons. 1734 22

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kappaB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.
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PMID:Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells. 1759 97

Acidosis has been shown to induce depletion of bone calcium from the body. This calcium release process is thought to be partially cell mediated. In an organ culture of bone, acidic pH has been shown to induce cyclooxygenase-2 (COX-2) induction and prostaglandin E(2) (PGE(2)) production, resulting in stimulation of bone calcium release. However, the molecular mechanisms whereby osteoblasts sense acidic circumstances and thereby induce COX-2 induction and PGE(2) production remain unknown. In this study, we used a human osteoblastic cell line (NHOst) to characterize cellular activities, including inositol phosphate production, intracellular Ca(2+) concentration ([Ca(2+)](i)), PGE(2) production, and COX-2 mRNA and protein expression, in response to extracellular acidification. Small interfering RNA (siRNA) specific to the OGR1 receptor and specific inhibitors for intracellular signaling pathways were used to characterize acidification-induced cellular activities. We found that extracellular acidic pH induced a transient increase in [Ca(2+)](i) and inositol phosphate production in the cells. Acidification also induced COX-2 induction, resulting in PGE(2) production. These proton-induced actions were markedly inhibited by siRNA targeted for the OGR1 receptor and the inhibitors for G(q/11) protein, phospholipase C, and protein kinase C. We conclude that the OGR1/G(q/11)/phospholipase C/protein kinase C pathway regulates osteoblastic COX-2 induction and subsequent PGE(2) production in response to acidic circumstances.
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PMID:Cyclooxygenase-2 expression and prostaglandin E2 production in response to acidic pH through OGR1 in a human osteoblastic cell line. 1830 4

Prostaglandins, in particular PGE(2) and prostacyclin PGI(2) have diverse biological effects. Most importantly, they are involved in inflammation and pain. Prostaglandins in nano- and micromolar concentrations sensitize nerve cells, i.e. make them more sensitive to electrical or chemical stimuli. Sensitization arises from the effect of prostaglandins on ion channels and occurs both at the peripheral terminal of nociceptors at the site of tissue injury (peripheral sensitization) and at the synapses in the spinal cord (central sensitization). The first step is the binding of prostaglandins to receptors in the cell membrane, mainly EP and IP receptors. The receptors couple via G proteins to enzymes such as adenylate cyclase and phospholipase C (PLC). Activation of adenylate cyclase leads to increase of cAMP and subsequent activation of protein kinase A (PKA) or PKA-independent effects of cAMP, e.g. mediated by Epac (=exchange protein activated by cAMP). Activation of PLC causes increase of inositol phosphates and increase of cytosolic calcium. This article summarizes the effects of PGE(2), PGE(1), PGI2 and its stable analogues on non-selective cation channels and sodium, potassium, calcium and chloride channels. It describes the mechanism responsible for the facilitatory or inhibitory prostaglandin effects on ion channels. Understanding these mechanisms is essential for the development of useful new analgesics.
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PMID:The action of prostaglandins on ion channels. 1861 37

Recent studies suggest that the epithelium might modulate the contractility of smooth muscle. However, the mechanisms underlying this regulation are unknown. The present study investigated the regulation of smooth muscle contraction by the epithelium in rat vas deferens and the possible factor(s) involved. Exogenously applied ATP inhibited electrical field stimulation (EFS)-evoked smooth muscle contraction in an epithelium-dependent manner. As the effects of ATP on smooth muscle contractility were abrogated by inhibitors of prostaglandin synthesis, but not by those of nitric oxide synthesis, prostaglandins might mediate the effects of ATP. Consistent with this idea, PGE(2) inhibited EFS-evoked smooth muscle contraction independent of the epithelium, while ATP and UTP induced the release of PGE(2) from cultured rat vas deferens epithelial cells, but not smooth muscle cells. The ATP-induced PGE(2) release from vas deferens epithelial cells was abolished by U73122, an inhibitor of phospholipase C (PLC) and BAPTA AM, a Ca(2+) chelator. ATP also transiently increased [Ca(2+)](i) in vas deferens epithelial cells. This effect of ATP on [Ca(2+)](i) was independent of extracellular Ca(2+), but abolished by the P2 receptor antagonist RB2 and U73122. In membrane potential measurements using a voltage-sensitive dye, PGE(2), but not ATP, hyperpolarized vas deferens smooth muscle cells and this effect of PGE(2) was blocked by MDL12330A, an adenylate cyclase inhibitor, and the chromanol 293B, a blocker of cAMP-dependent K(+) channels. Taken together, our results suggest that ATP inhibition of vas deferens smooth muscle contraction is epithelium dependent. The data also suggest that ATP activates P2Y receptor-coupled Ca(2+) mobilization leading to the release of PGE(2) from epithelial cells, which in turn activates cAMP-dependent K(+) channels in smooth muscle cells leading to the hyperpolarization of membrane voltage and the inhibition of vas deferens contraction. Thus, the present findings suggest a novel regulatory mechanism by which the epithelium regulates the contractility of smooth muscle.
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PMID:Regulation of smooth muscle contractility by the epithelium in rat vas deferens: role of ATP-induced release of PGE2. 1901 Nov 31

Accumulating evidence has indicated that mast cells can modulate a wide variety of immune responses. Migration and adhesion play a critical role in regulation of tissue mast cell function, in particular, under inflammatory conditions. We previously demonstrated that prostaglandin (PG) E(2) stimulates adhesion of a mouse mastocytoma cell line, P-815, to the Arg-Gly-Asp (RGD)-enriched matrix through cooperation between two PGE(2) receptor subtypes: EP3 and EP4 (Hatae N, Kita A, Tanaka S, Sugimoto Y, Ichikawa A. J Biol Chem 278: 17977-17981, 2003). We here investigated PGE(2)-induced adhesion of IL-3-dependent bone marrow-derived cultured mast cells (BMMCs). In contrast to the elevated cAMP-dependent adhesion of P-815 cells, EP3-mediated Ca(2+) mobilization plays a pivotal role in PGE(2)-induced adhesion of BMMCs. Adhesion and Ca(2+) mobilization induced by PGE(2) were abolished in the Ptger3(-/-) BMMCs and were significantly suppressed by treatment with pertussis toxin, a phospholipase C inhibitor, U-73122, and a store-operated Ca(2+) channel inhibitor, SKF 36965, indicating the involvement of G(i)-mediated Ca(2+) influx. We then investigated PGE(2)-induced adhesion of peritoneal mast cells to the RGD-enriched matrix. EP3 subtype was found to be the dominant PGE receptor that expresses in mouse peritoneal mast cells. PGE(2) induced adhesion of the peritoneal mast cells of the Ptger3(+/+) mice, but not that of the Ptger3(-/-) mice. In rat peritoneal mast cells, PGE(2) or an EP3 agonist stimulated both Ca(2+) mobilization and adhesion to the RGD-enriched matrix. These results suggested that the EP3 subtype plays a pivotal role in PGE(2)-induced adhesion of murine mast cells to the RGD-enriched matrix through Ca(2+) mobilization.
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PMID:Essential role of EP3 subtype in prostaglandin E2-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix. 1881 28

Fatty acids serve vital functions as sources of energy, building materials for cellular structures, and modulators of physiological responses. Therefore, this study examined the effect of linoleic acid on glucose production and its related signal pathways in primary cultured chicken hepatocytes. Linoleic acid (double-unsaturated, long chain) increased glucose production in a dose (> or =10(-4) M)- and time (> or =8 h)-dependent manner. Both oleic acid (monounsaturated, long chain) and palmitic acid (saturated, long chain) also increased glucose production, whereas caproic acid (saturated, short chain) failed to increase glucose production. Linoleic acid increased G protein-coupled receptor 40 (GPR40; also known as free fatty acid receptor-1) protein expression and glucose production that was blocked by GPR40-specific small interfering RNA. Linoleic acid increased intracellular calcium concentration, which was blocked by EGTA (extracellular calcium chelator)/BAPTA-AM (intracellular calcium chelator), U-73122 (phospholipase C inhibitor), nifedipine, or methoxyverapamil (L-type calcium channel blockers). Linoleic acid increased cytosolic phospholipase A(2) (cPLA(2)) phosphorylation and the release of [(3)H]-labeled arachidonic acid. Moreover, linoleic acid increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of prostaglandin E(2) (PGE(2)). The increase in PGE(2) production subsequently stimulated peroxisome proliferator-activated receptor (PPAR) expression, and MK-886 (PPAR-alpha antagonist) and GW-9662 (PPAR-delta antagonist) inhibited glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In addition, linoleic acid-induced glucose production was blocked by inhibition of extracellular and intracellular calcium, cPLA(2), COX-2, or PPAR pathways. In conclusion, linoleic acid promoted glucose production via Ca(2+)/PLC, cPLA(2)/COX-2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes.
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PMID:Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes. 1884 27


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