Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which red wine polyphenolic compounds (RWPCs) induced endothelium-dependent relaxation were investigated in rat thoracic aorta rings with endothelium. RWPCs produced relaxation that was prevented by the nitric oxide (NO) synthase inhibitor, N(omega)-nitro-L-arginine-methyl-ester. This relaxation was abolished in the absence of extracellular calcium in the medium or in the presence of the Ca2+ entry blocker, La3+, but it was not affected by the nonselective K+ channels blocker, tetrabutylammonium. N-Ethyl-maleimide (NEM), a sulfhydryl alkylating agent, abolished vasorelaxation produced by RWPCs and acetylcholine but not that produced either by the sarcoendoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) pump inhibitor, cyclopyazonic acid (CPA) or the calcium ionophore, ionomycin. Neither pertussis toxin (PTX) nor cholera toxin (CTX) inhibited the vasorelaxant effect of RWPC. The effect of RWPC was not affected by the phospholipase C (PLC) blocker, L-alpha-glycerophospho-D-myo-inositol 4-monophosphate (Gro-pip), and the phospholipase A2 pathway blockers, quinacrine and ONO-RS-082. Finally, the protein kinase C (PKC) inhibitor, GF 109203X, and tyrosine kinase inhibitors, tyrphostin A-23 and genistein, did not impair the response to RWPCs. These results suggest that RWPCs produce endothelium-NO-derived vasorelaxation through an extracellular Ca2+-dependent mechanism via an NEM-sensitive pathway. They also show that PTX- or CTX-sensitive G proteins, activation of PLC or PLA2 pathways, PKC, or tyrosine kinase may not be involved.
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PMID:Mechanism of endothelial nitric oxide-dependent vasorelaxation induced by wine polyphenols in rat thoracic aorta. 1002 33

During gamete interaction, sperm acrosome reaction (AR) induced by oocyte investment is a prerequisite event for the spermatozoa to pass through the zona pellucida (ZP), fuse with and penetrate the oocyte. Progesterone (P4), secreted by cumulus cells, is an important cofactor for the occurrence of this exocytosis event. The AR results from the fusion between outer acrosomal and plasma membranes, leading to inner acrosomal membrane exposure. Binding of agonists, P4 or ZP3 glycoprotein, to plasma membrane sperm receptors activates intraspermatic signals and enzymatic pathways involved in the AR. Among the proteins or glycoproteins described as potential sperm receptors for ZP, Gi/Go protein-coupled and tyrosine kinase receptors have been described. Sperm receptors for P4 are poorly characterized, except a putative GABA(A)-like receptor. ZP- and P4-promoted AR is mediated by an obligatory intracellular calcium increase, appearing first at the acrosome equatorial segment and spreading throughout the head. The plasma membrane channels involved in calcium entry are operated by a plasma membrane depolarization and protein phosphorylations mediated by protein kinase C and tyrosine kinase protein. Part of the calcium increase could also be due to intracellular store release through IP3- and nucleotide (cAMP)-gated channels. Besides adenylate cyclase and phospholipase C activations, intracellular calcium increase also stimulates PLA2 activity and actin depolymerization, leading to membrane fusion. Evaluation of AR by staining or fluorescent probes can be useful to predict fertilization success and to direct the therapeutic strategy in male infertility.
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PMID:The acrosome reaction in human spermatozoa. 1104 13

Using an in vitro traumatic injury model, we examined the effects of mechanical (stretch) injury on intracellular Ca2+ store-mediated signaling in cultured cortical neurons using fura-2. We previously found that elevation of [Ca2+](i) by the endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, was abolished 15 min post-injury. In the current studies, pre-injury inhibition of phospholipase C with neomycin sulfate maintained Ca2+-replete stores 15 min post-injury, suggesting that the initial injury-induced store depletion may be due to increased inositol trisphosphate production. Thapsigargin-stimulated elevation of [Ca2+](i) returned with time after injury and was potentiated at 3 h. Stimulation with thapsigargin in Ca2+-free media revealed that the size of the Ca2+ stores was normal at 3 h post-injury. However, Ca2+ influx triggered by depletion of intracellular Ca2+ stores (capacitative Ca2+ influx) was enhanced 3 h after injury. Enhancement was blocked by inhibitors of cytosolic phospholipase A2 and cytochrome P450 epoxygenase. Since intracellular Ca2+ store-mediated signaling plays an important role in neuronal function, the observed changes may contribute to dysfunction produced by traumatic brain injury. Additionally, our results suggest that capacitative Ca2+ influx may be mediated by both conformational coupling and a diffusible messenger synthesized by the combined action of cytosolic PLA2 and P450.
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PMID:Traumatic injury of cortical neurons causes changes in intracellular calcium stores and capacitative calcium influx. 1105 Jan 3

c-Fos, a transcription factor, associates to endoplasmic reticulum and modulates phospholipid biosynthesis. Its surface thermodynamic properties allow it to differentially interact with phospholipid monolayers with a selective dependence on the lipid polar head group and the lateral surface pressure. We explored the c-Fos ability to modulate phospholipid degradation by phospholipases (ppPLA2, Bacillus cereus PLC, and sphingomyelinase) using the monolayer technique. Experiments conducted under constant packing conditions show that c-Fos modulates phospholipase activity in a finely tuned way, depending on the membrane intermolecular packing. Surface lateral pressures above 12-16 mN/m induce c-Fos to activate phospholipase A2 and sphingomyelinase, and abolish phospholipase C activity. The effects of c-Fos on other steps of the catalytic process, lag-time and extent, are synergic with those on activity. We show for the first time that c-Fos participates in modulating phospholipid degradation and that it can affect the formation of lipid second messenger products by PLA2, PLC, and sphingomyelinase.
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PMID:c-Fos is a surface pressure-dependent diverter of phospholipase activity. 1212 89

Steroid hormones regulate target cells through traditional nuclear mechanisms as well as by membrane mechanisms. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 bind membrane receptors (mVDR) and mediate their effects on the physiological responses of musculoskeletal cells via protein kinase C (PKC). In cultures of costochondral growth plate chondrocytes, 1alpha,25(OH)2D3 binds the 1,25-mVDR in growth zone cells, activating phospholipase C (PLC), leading to diacylglycerol (DAG) production and PKC translocation to the plasma membrane. It also activates PLA2, increasing arachidonic acid release and prostaglandin synthesis. 24R,25(OH)2D3 binds its membrane receptor in resting zone chondrocytes, activating phospholipase D (PLD), and increasing DAG and PKC activity, but translocation does not occur. PLA2 activity is decreased, reducing arachidonic acid and prostaglandin production. 17Beta-estradiol (E2) activates PKC in both cartilage cells, but DAG is not involved. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 also increase PKC in osteoblasts in a cell-specific manner. Antibodies to the 1,25-mVDR block PKC activation. Membrane-mediated events influence gene expression via signaling cascades, including the ERK1/2 MAP kinases. The ability of steroid hormones to initiate events nongenomically is important for regulation of matrix vesicle (MV) function in the extracellular matrix. MVs have mVDRs, but ligand binding inhibits PKC-zeta (PKCzeta) via a mechanism that differs from PKCalpha activation in the plasma membranes. Treatment of MVs from growth zone chondrocyte cultures with 1alpha,25(OH)2D3 releases stromelysin-1 (MMP-3) and increases TGF-beta activation. MMP-3 is also involved in proteoglycan degradation, facilitating calcification. 24R,25(OH)2D3 inhibits PKCzeta in MV from resting zone cell cultures and inhibits MMP-3 release. Chondrocytes and osteoblasts produce 1,25(OH)2D3, 24,25(OH)2D3, and E2; thus, locally produced steroids may function as autocrine regulators of matrix events, including matrix vesicle enzyme activity and matrix protein remodelling during longitudinal growth, calcification, and growth factor activation.
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PMID:Steroid hormone action in musculoskeletal cells involves membrane receptor and nuclear receptor mechanisms. 1295 86

We have reexamined the muscarinic receptor subtype mediating carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A2 and of intra- and extracellular Ca2+ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M2 receptor-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M3 receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by the phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)-amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122; 10 microM). Nevertheless, U 73,122 (1-10 microM) did not significantly affect carbachol-stimulated bladder contraction. Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of carbachol-induced bladder contraction. The cytosolic PLA2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited carbachol-induced contraction at a concentration of 300 microM, but the cyclooxygenase inhibitor indomethacin (1-10 microM) remained without effect. The Ca2+ entry blocker nifedipine (10-100 nM) almost completely inhibited carbachol-induced bladder contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96,365; 10 microM), an inhibitor of store-operated Ca2+ channels, caused little inhibition. We conclude that carbachol-induced contraction of rat bladder largely depends on Ca2+ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA2, and store-operated Ca2+ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.
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PMID:Signal transduction underlying carbachol-induced contraction of rat urinary bladder. I. Phospholipases and Ca2+ sources. 1453 54

Histamine produced concentration-dependent contractions in cat duodenal smooth muscle cells that were obtained by enzymatic digestion of smooth muscle with collagenase F. Pyrilamine, an H1 receptor antagonist, inhibited the contractile response while famotidine, an H2 receptor antagonist, augmented it. In cells with selectively preserved H1 receptors, produced by pretreatment with pyrilamine followed by inactivation of all unprotected receptors with N-ethylmaleimide, histamine-induced contraction was significantly augmented as compared with control cells. Pertussis toxin (PTX) had no effect on contraction, suggesting that the H1 receptor is coupled to a PTX-insensitive G protein. Gi2, Gi3, Go, Gs, and Gq subunits were present in cat duodenum, and histamine-induced contraction was inhibited by Gq antibody after cell permeabilization. Neomycin, a PLC inhibitor, inhibited the histamine-induced cell contraction, but not rhoCMB, a PLD inhibitor, or DEDA, a PLA2 inhibitor. Heparin, an IP3 receptor inhibitor, inhibited contraction whereas chelerythrine, a PKC inhibitor, had no effect. We conclude that histamine-induced contraction in cat duodenal smooth muscle cells is mediated by H1 receptors coupled to a PTX-insensitive Gq protein and results in activation of phosphatidylinositol-specific phospholipase C (PI-PLC).
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PMID:Signaling via histamine receptors in cat duodenal smooth muscle cells. 1465 Dec 59

Contraction of esophageal (Eso) and lower esophageal sphincter (LES) circular muscle depends on distinct signal-transduction pathways. ACh-induced contraction of Eso muscle is linked to phosphatidylcholine metabolism, production of diacylglycerol and arachidonic acid (AA), and activation of the Ca(2+)-insensitive PKCepsilon. Although PKCepsilon does not require Ca(2+) for activation, either influx of extracellular Ca(2+) or release of Ca(2+) from stores is needed to activate the phospholipases responsible for hydrolysis of membrane phospholipids and production of second messengers, which activate PKCepsilon. In contrast, the LES uses two distinct intracellular pathways: 1) a PKC-dependent pathway activated by low doses of agonists or during maintenance of spontaneous tone, and 2) a Ca(2+)-calmodulin-myosin light chain kinase (MLCK)-dependent pathway activated in response to maximally effective doses of agonists during the initial phase of contraction. The Ca(2+) levels, released by agonist-induced activity of phospholipase C, determine which contractile pathway is activated in the LES. The Ca(2+)-calmodulin-MLCK-dependent contractile pathway has been well characterized in a variety of smooth muscles. The steps linking activation of PKC to myosin light chain (MLC20) phosphorylation and contraction, however, have not been clearly defined for LES, Eso, or other smooth muscles. In addition, in LES circular muscle, a low-molecular weight pancreatic-like phospholipase A2 (group I PLA2) causes production of AA, which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to heterotrimeric G proteins to induce activation of phospholipases and production of second messengers to maintain contraction of LES circular muscle. We have examined the signal-transduction pathways activated by PGF(2alpha) and by thromboxane analogs during the initial contractile phase and found that these pathways are the same as those activated by other agonists. In response to low doses of agonists or during maintenance of tone, presumably due to low levels of calcium release, a PKC-dependent pathway is activated, whereas at high doses of PGF(2alpha) and thromboxane analogs, in the initial phase of contraction, calmodulin is activated, PKC activity is reduced, and contraction is mediated, in part, through a Ca(2+)-calmodulin-MLCK-dependent pathway. The PKC-dependent signaling pathways activated by PGF(2alpha) and by thromboxanes during sustained LES contraction, however, remain to be examined, but preliminary data indicate that a distinct PKC-dependent pathway may be activated during maintenance of tonic contraction, which is different from the one activated during the initial contractile response. The initial contractile response to low levels of agonists depends on activation of G(q). Sustained contraction in response to PGF(2alpha) may involve activation of the monomeric G protein RhoA, because the contraction is inhibited by the RhoA-kinase antagonist Y27632. This shift in signal-transduction pathways between initial and sustained contraction has been recently reported in intestinal smooth muscle.
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PMID:Signal-transduction pathways that regulate smooth muscle function I. Signal transduction in phasic (esophageal) and tonic (gastroesophageal sphincter) smooth muscles. 1570 19

Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in phospholipid metabolism occur during cellular differentiation, proliferation, and apoptosis, but the molecular mechanism involved in the above processes remains unknown. We propose that the coordinated expression of different genes responsible for the expression of transcription factors, neurotrophins, and cytokines, along with lipid mediators generated by the action of phospholipases A2, C, and D (PLA2, PLC, and PLD), play a very important role in differentiation, proliferation, and apoptosis. The purpose of this minireview is to discuss recent developments in PLA2, PLC, and PLD-mediated signaling in the nucleus of LA-N-1 neuroblastoma cell cultures. In brain tissue, arachidonic acid is mainly released by the action of PLA2 and phospholipase C/diacylglycerol lipase (PLC/DAG-lipase) pathways. We have used LA-N-1 cell cultures to study activities of PLA2, C, and D during retinoic acid (RA)-mediated differentiation. The treatment of LA-N-1 cells with RA produces an increase in PLA2 activity in the nuclear fraction. This increase in PLA2 activity can be prevented with BMS493, a pan retinoic acid receptor antagonist, suggesting that RA-induced stimulation of PLA2 activity is a RA receptor-mediated process. The treatment of LA-N-1 cells with 12-O-tetradecanoyl-phorbol-13 acetate (TPA) and RA increases diacylglycerol (DAG) levels indicating the stimulation of PLC activity. This stimulation is blocked by D609, tricyclodecan-9-yl potassium xanthate, a competitive PtdCho-specific PLC inhibitor. LA-N-1 cells also contain DAG-and monoacylglycerol (MAG) lipase activities. Two isoforms of PLD, oleate-dependent and TPA-dependent, are also present in LA-N-1 cell homogenates. RA stimulates the oleate-dependent isoform of PLD, whereas RA does not stimulate the TPA-dependent isoform. Our studies have indicated that lipid mediators generated by the action of PLA2, PLC, and PLD on nuclear phospholipids markedly affect neuritic outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that RA receptors coupled with PLA2, PLC, and PLD activities in the nucleus may play an important role in the redistribution of arachidonic acid and its metabolites and DAG in nuclear and non-nuclear neuronal membranes during differentiation and growth suppression.
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PMID:Signaling and interplay mediated by phospholipases A2, C, and D in LA-N-1 cell nuclei. 1618 11

Human neutrophils are highly specialised for their primary function, i.e. phagocytosis and destruction of microorganisms. Leukocyte recruitment to sites of inflammation and infection is dependent upon the presence of a gradient of locally produced chemotactic factors. The bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) was one of the first of these to be identified and is a highly potent leukocyte chemoattractant. It interacts with its receptor on the neutrophil membrane, activating these cells through a G-protein-coupled pathway. Two functional fMLP receptors have thus far been cloned and characterized, namely FPR (formyl peptide receptor) and FPRL1 (FPR like-1), with high and low affinities for fMLP, respectively. FMLP is known to activate phospholipase C (PLC), PLD, PLA2 and phosphatidylinositol-3-kinase (PI3K), and it also activates tyrosine phosphorylation. The second messengers resulting from the fMLP receptor interaction act on various intracellular kinases, including protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs). The activation of these signal transduction pathways is known to be responsible for various biochemical responses which contribute to physiological defence against bacterial infection and cell disruption. This review will consider the ability of selective analogues (ligands able to discriminate between different biological responses) to activate a single spectrum of signal transduction pathways capable of producing a unique set of cellular responses, hypothesising that a distinctive imprint of signal protein activation may exist. Through more complete understanding of intracellular signaling, new drugs could be developed for the selective inflammatory blockade.
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PMID:Signal transduction pathways triggered by selective formylpeptide analogues in human neutrophils. 1651 93


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