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)

Effects of 2,3-butanedione-2-monoxime (BDM) on the contraction of intact and skinned smooth muscles from guinea-pig portal vein were examined. In intact preparations loaded with fura-2, 5-10 mM BDM markedly suppressed Ca2+ transients and force developments induced by 154 mM potassium and by phenylephrine (0.1 mM). On the other hand, in Ca(2+)-free depolarizing solution, BDM did not suppress phenylephrine (0.1 mM)-induced Ca2+ transient and force development. In skinned preparations obtained with Staphylococcus aureus alpha-toxin treatment, BDM did not markedly affect active force development. The above results indicate that BDM suppresses contraction of the portal vein mainly by the inhibition of voltage-dependent cytosolic Ca2+ transients. An additional result suggests that BDM suppresses the force-enhancing effect of alpha 1-adrenergic agents on the contractile elements.
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PMID:Effect of 2,3-butanedione monoxime on smooth-muscle contraction of guinea-pig portal vein. 813 62

An antiallergic drug, pemirolast potassium (TBX) at concentrations between 0.01 and 10 micrograms/ml inhibited antigen (Ag)-stimulated degranulation in RBL-2H3 cells, which have the properties of mucosal mast cells. At the same concentrations, the drug suppressed both the formation of inositol 1,4,5-trisphosphate and the mobilization of Ca2+, indicating the prevention of phospholipase C activation. The production of 1,2-diacylglycerol and phosphatidic acid, which was mainly due to phosphatidylcholine hydrolysis, was also suppressed. Moreover, TBX reduced Ag-induced liberation of arachidonic acid, a precursor of eicosanoids, implying the inhibition of phospholipase A2. These data suggest that TBX inhibits the activation of phospholipase C, leading to decreased formation of the signal transducing molecules necessary for cell activation.
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PMID:An antiallergic drug, pemirolast potassium, inhibits inositol 1,4,5-trisphosphate production and Ca2+ mobilization in antigen-stimulated rat basophilic leukemia (RBL-2H3) cells. 814 17

Various neurotransmitters, hormones and other modulators involved in intercellular communication exert their biological action at receptors coupled to phospholipase C (PLC). This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) to inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DG) which act as second messengers. In the organ of Corti of the guinea pig, the InsP3 second messenger system is linked to muscarinic cholinergic and P2y purinergic receptors. However, nothing is known about the InsP3 second messenger system in the vestibule. In this study, the receptor-mediated release of inositol phosphates (InsPs) in the vestibular sensory epithelia was compared to that in the cochlear sensory epithelia of Fischer-344 rats. After preincubation of the isolated intact tissues with myo-[3H]inositol, stimulation with the cholinergic agonist carbamylcholine or the P2 purinergic agonist ATP-gamma-S resulted in a concentration-dependent increase in the formation of [3H]InsPs in both epithelia. Similarly, the muscarinic cholinergic agonist muscarine enhanced InsPs release in both organs, while the nicotinic cholinergic agonist dimethylphenylpiperadinium (DMPP) was ineffective. The muscarinic cholinergic antagonist atropine completely suppressed the InsPs release induced by carbamylcholine, while the nicotinic cholinergic antagonist mecamylamine was ineffective. Potassium depolarization did not alter unstimulated or carbamylcholine-stimulated release of InsPs in either organ. In both tissues, the P2 purinergic agonist alpha,beta-methylene ATP also increased InsPs release, but the P1 purinergic agonist adenosine did not. These results extend our previous observations in the organ of Corti of the guinea pig to the rat and suggest a similar control of the InsP3 second messenger system in the vestibular sensory epithelia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Receptor-mediated release of inositol phosphates in the cochlear and vestibular sensory epithelia of the rat. 822 41

Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative coupling with adenylate cyclase, they are also coupled with potassium and calcium channels, leading to a decreased intracellular calcium concentration. In addition, D2 dopamine receptors also modulate phospholipase activities. Dopamine inhibits inositol phosphate production, through two distinct mechanisms. One of them could represent a direct negative coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospholipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a single gene are present in lactotroph cells. After transfection in CH4C1 cells the two isoforms are coupled with adenylate cyclase while only the shortest isoform appears negatively coupled to phospholipase C. Functional D2 dopamine receptors are present in human prolactinomas. Resistance to bromocriptine therapy is associated with a decrease density of these receptors in the tumor. In addition, the ratio of the two receptor isoforms (measured by PCR) is different in responsive and resistant tumors. Furthermore, the activity of Gi/Go proteins coupled to adenylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.
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PMID:[Membrane receptors and coupling proteins in adenohypophyseal cells]. 824 19

1. Acetylcholine (ACh) produces two membrane current changes when applied to NG108-15 mouse neuroblastoma x rat glioma hybrid cells transformed (by DNA transfection) to express m1 muscarinic receptors: it activates a Ca(2+)-dependent K+ conductance, producing an outward current, and it inhibits a voltage-dependent K+ conductance (the M conductance), thus diminishing the M-type voltage-dependent K+ current (IK(M)) and producing an inward current. The present experiments were undertaken to find out how far inhibition of IK(M) might be secondary to stimulation of phospholipase C, by recording membrane currents and intracellular Ca2+ changes with indo-1 using whole-cell patch-clamp methods. 2. Bath application of 100 microM ACh reversibly inhibited IK(M) by 47.3 +/- 3.2% (n = 23). Following pressure-application of 1 mM ACh, the mean latency to inhibition was 420 ms at 35 degrees C and 1.79 s at 23 degrees C. Latencies to inhibition by Ba2+ ions were 148 ms at 35 degrees C and 92 ms at 23 degrees C. 3. The involvement of a G-protein was tested by adding 0.5 mM GTP-gamma-S or 10 mM potassium fluoride to the pipette solution. These slowly reduced IK(M), with half-times of about 30 and 20 min respectively, and rendered the effect of superimposed ACh irreversible. Effects of ACh were not significantly changed after pretreatment for 24 h with 500 ng ml-1 pertussis toxin or on adding up to 10 mM GDP-beta-S to the pipette solution. 4. The role of phospholipase C and its products was tested using neomycin (to inhibit phospholipase C), inositol 1,4,5-trisphosphate (InsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4), heparin, and phorbol dibutyrate (PDBu) and staurosporin (to activate and inhibit protein kinase C respectively). Both neomycin (1 mM external) and InsP3 (100 microM intrapipette) inhibited the ACh-induced outward current and/or intracellular Ca2+ transient but did not block ACh-induced inhibition of IK(M). Intrapipette heparin (1 mM) blocked activation of IK(Ca) and reduced Ach-induced inhibitions of IK(M), but also reduced inhibition of ICa via endogeneous m4 receptors. PDBu (with or without intrapipette ATP) and staurosporin had no significant effects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:On the mechanism of M-current inhibition by muscarinic m1 receptors in DNA-transfected rodent neuroblastoma x glioma cells. 827 Nov 96

An investigation was undertaken of the mechanism by which oxyhemoglobin and its analog methemoglobin might cause cerebrovascular spasm. The effect of these compounds on the levels of intracellular inositol triphosphate and calcium in cultured primate cerebrovascular smooth-muscle cells and the contractile action of oxyhemoglobin on isolated rings of primate cerebral arteries were also examined. Oxyhemoglobin, but not methemoglobin, produces a transient but highly significant increase in the intracellular levels of inositol triphosphate. Intracellular calcium levels in these cells are increased by thrombin, aluminum tetrafluoride, and oxyhemoglobin, and the sustained elevation in intracellular calcium is prevented by ethyleneglycol tetra-acetic acid and the phospholipase C inhibitor neomycin. Removal of the oxyhemoglobin after as long as 48 hours' incubation with this compound allowed cells to rapidly reduce their intracellular calcium levels to near normal. Oxyhemoglobin produced contractions of isolated rings of both normal and spastic cerebral arteries, although the response of spastic vessels was significantly smaller. This effect was inhibited by neomycin. The addition of neomycin relaxed arteries that were contracted with oxyhemoglobin, 5-hydroxytryptamine, or potassium chloride. It is thus likely that activation of phospholipase C is a critical step in the development of vasospasm, but the transient nature of the response to inositol triphosphate suggests that the sustained contraction may arise from other phospholipase C-dependent mechanisms.
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PMID:Intracellular mechanisms involved in the responses of cerebrovascular smooth-muscle cells to hemoglobin. 828 65

In NG108-15 cells, bradykinin (BK) activates a potassium current (IK,BK) and inhibits the voltage-dependent calcium current (ICa,V). BK also stimulates a phosphatidylinositol-specific phospholipase C (PI-PLC). The subsequent release of inositol 1,4,5-trisphosphate and increase in intracellular calcium contribute to IK,BK, through activation of a calcium-dependent potassium current. In membranes from these cells, stimulation of PI-PLC by BK is mediated by Gq and/or G11, two homologous, pertussis toxin-insensitive G proteins. Here, we have investigated the role of Gq/11 in the electrical responses to BK. GTP gamma S mimicked and occluded both actions of BK, and both effects were insensitive to pertussis toxin. Perfusion of an anti-Gq/11 alpha antibody into the pipette suppressed IK,BK, but not the inhibition of ICa,V by BK. Thus, BK couples to IK,BK via Gq/11, but coupling to ICa,V is most likely via a different, pertussis toxin-insensitive G protein.
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PMID:Bradykinin modulates potassium and calcium currents in neuroblastoma hybrid cells via different pertussis toxin-insensitive pathways. 829 55

Evidence has shown an activation of phosphatidylinositol 4,5-bisphosphate (PIP2) specific phospholipase C (PtdIns-PLC) by light in the vertebrate retina and rod outer segments (ROS), suggesting important roles for its two metabolites, 1,2-diacylglycerol (DG) and inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. DG activates protein kinase C (PKC) and Ins(1,4,5)P3 releases bound intracellular calcium. Since Ca2+ plays an important role in light adaptation, the presence of Ins(1,4,5)P3 receptors in ROS may indicate a regulatory role of Ins(1,4,5)P3 to the free Ca2+ content. In the present study, we investigated the Ins(1,4,5)P3 receptors in whole retinal membranes and several subcellular fractions prepared from bovine retinas. Scatchard analyses of binding data for retinal membrane preparations showed a single, high-affinity binding site with equilibrium dissociation constant (Kd) of 24 +/- 2 nM and maximal binding capacity (Bmax) of 353 +/- 15 fmol/mg protein at pH 7.4. Specific binding was found in both small and large synaptosomal preparations representing inner and outer plexiform layers, respectively. A detectable, but low abundance of Ins(1,4,5)P3-specific binding in ROS was observed at both pH 7.4 and 8.3, but no specific binding of Ins(1,4,5)P3 was found in isolated outer segment discs. The binding of Ins(1,4,5)P3 in ROS was reduced by addition of ATP, suggesting a regulatory role for this nucleotide. Addition of calcium, sodium, and potassium ions also reduced specific binding of Ins(1,4,5)P3. Immunocytochemical studies indicate intense staining in the inner segment and extending to the ROS. Inner and outer plexiform layers were also stained. These findings show that the Ins(1,4,5)P3 receptor is present in photoreceptor cells and inner and outer plexiform layers in the vertebrate retina.
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PMID:Inositol-1,4,5-trisphosphate receptors in the vertebrate retina. 830 16

SHR (spontaneously hypertensive rat) is the most popular genetic hypertensive model rat. Using the F2 progeny obtained from SHR and normotensive rats, for example, WKY (Wistar-Kyoto rat), many cosegregation studies to find the genes responsible for blood pressure have been done. In this review, we present some studies using F2 rats concerning candidate genes, renin, kallikrein, sodium potassium-ATPase, heat shock protein 70, angiotensin converting enzyme, phospholipase C-delta 1 and SA gene to show whether these genes really associate with blood pressure. We discuss the signification of these genes in the process of producing SHR and stroke-prone SHR from WKY. We hope these studies will lead to identify the mechanism of human essential hypertension.
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PMID:[Cosegregation studies in spontaneously hypertensive rats]. 832 Aug 40

The cellular transduction mechanisms underlying the response of blood vessels to mechanical forces such as pressure or stretch are largely unknown. In this report we test the hypothesis that myogenic tone in the cerebral circulation is coupled to activation of phospholipase C (PLC) and G proteins. Rat posterior cerebral arteries (luminal diam 189 +/- 4 microns) were cannulated in an arteriograph and allowed to develop myogenic tone at 75 mmHg (122 +/- 6 microns; P < 0.01). Exposure to U-73122, an inhibitor of PLC, produced concentration-dependent vasodilation, with near-maximal (> 90%) inhibition at concentrations > 3 microM (50% inhibitory concentration = 0.8 +/- 0.04 microM). The action of U-73122 was confirmed by demonstrating that constrictor responses to serotonin (PLC mediated) could be significantly attenuated or abolished at concentrations (0.5-1 microM) that were ineffective in antagonizing potassium depolarization or indolactam-induced constrictions (both PLC independent). Incubation in pertussis toxin (100 ng/ml, 2-2.5 h), an inhibitor of some G protein subtypes, reduced myogenic tone by 74 +/- 12%, with luminal diameters increasing from 129 +/- 7 to 160 +/- 7 microns. Conversely, nonspecific G protein activation using AlF-4 (NaF+AlCl3, 0.5-5 mM) significantly increased myogenic tone by 86 +/- 9%, reducing luminal diameters from 132 +/- 6 to 88 +/- 8 microns (P < 0.01). Together, these findings suggest that 1) PLC is activated in arteries that possess myogenic tone, 2) pharmacological inhibition of PLC results in a virtual loss of pressure-induced constriction, and 3) G proteins may modulate mechanotransduction through pathways superimposed on basal myogenic tone.
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PMID:Myogenic tone is coupled to phospholipase C and G protein activation in small cerebral arteries. 834 61


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