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)

Neuronal nitric oxide synthase (nNOS; EC 1.14.13.39) activity in supernatant of rat cerebellum homogenate was unstable and chelating reagent protected the activity from the rapid decrease. The main target ion of the chelating reagent was found to be Ca2+. Although the enzyme was very unstable after purification by the procedures including DEAE-cellulose chromatography and ammonium sulfate precipitation, the inactivation was neither accelerated by addition of Ca2+ nor protected by EGTA. Upon addition of boiled supernatant of rat cerebellum homogenate, this purified enzyme became more active and stable, but rapid inactivation occurred again by addition of Ca2+, suggesting the existence of previously unreported Ca2(+)-dependent stabilizer / activator in the boiled supernatant. This factor was concentrated by organic solvent and the effects on the enzyme were completely canceled by addition of Ca2+ or phospholipase C treatment.
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PMID:Calcium-dependent inactivation of neuronal nitric oxide synthase: evidence for the existence of stabilization / activation factor. 917 96

The purpose of this study was to elucidate the mechanism by which acetylcholine (ACh) promotes prostacyclin (PGI2) production in cultured coronary endothelial cells (CEC) of the rabbit heart. ACh-induced production of PGI2, measured as immunoreactive 6-keto-PGF1alpha, was enhanced by increasing the extracellular calcium (Ca++) concentration and reduced by Ca++ depletion. The receptor-operated Ca++ channel blocker SK&F96365, but not the voltage-dependent Ca++ channel blockers verapamil or nifedipine, attenuated ACh-induced 6-keto-PGF1alpha production and the associated rise in cytosolic Ca++. Thapsigargin, which depleted Ca++ accumulation from the intracellular Ca++ store, did not prevent the ACh-induced rise in cytosolic Ca++. In the absence of extracellular Ca++, ACh and ATP increased cytosolic Ca++ but did not alter 6-keto-PGF1alpha production. In permeabilized CEC, guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) but not ACh enhanced 6-keto-PGF1alpha synthesis. ACh increased 6-keto-PGF1alpha production in the presence of GTP-gamma-S. These effects of GTP-gamma-S were attenuated by guanosine 5'-O-(2-thiotriphosphate). In the absence of extracellular Ca++, ACh or ATP increased cytosolic Ca++ in cells permeabilized with beta-escin and loaded with GTP-gamma-S; this effect was attenuated by guanosine 5'-O-(2-thiotriphosphate). The effect of ATP but not ACh to mobilize intracellular Ca++ or increase 6-keto-PGF1alpha was inhibited by pertussis toxin. The phospholipase C inhibitor D609, which attenuated ACh- and ATP-induced mobilization of intracellular Ca++, did not alter 6-keto-PGF1alpha production. The NO synthase inhibitor N-monomethyl-arginine also failed to alter ACh-induced 6-keto-PGF1alpha synthesis. These data suggest that, in CEC of the rabbit heart, ACh stimulates prostacyclin production via a pertussis toxin-insensitive G protein and by increasing the influx of extracellular Ca++ through a G protein-independent receptor-operated Ca++ channel.
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PMID:Signal transduction mechanism(s) involved in prostacyclin production elicited by acetylcholine in coronary endothelial cells of rabbit heart. 922 47

The possible role of altered humoral immune response in the pathogenesis of the chronic chagasic cardioneuromyopathy was examined by analyzing the interaction of IgG from T. cruzi infected patients with cardiac muscarinic acetylcholine receptors (mAChR). Human chagasic IgG by activating cardiac M2 mAChR, simulated the agonist actions triggering negative inotropic effect, inositol phosphate accumulation, nitric oxide synthase stimulation and increased production of cyclic GMP. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase activities; prevented chagasic IgG effects on signaling pathways involved in M2 mAChR activation. In addition, sodium nitroprusside or 8-bromo cyclic GMP, mimicked the chagasic IgG effect associated with cholinergic-mediated cellular transmembrane signals. Moreover, these chagasic IgG immunoprecipitated the mAChRs solubilized from cardiac membranes. By means of SDS-PAGE and immunoblotting analysis, chagasic sera recognized a band of 70-75 kDa. The major protein recognized by chagasic IgG had an Rf coincident with the peak of [3H] propylbenzilylcholine mustard with an apparent molecular weight similar to that of mAChRs, which disappeared in the presence of atropine. The specificity of this interaction was checked by immunoprecipitation of rat cardiac mAChR and immunoblotting of pure human M2 mAChRs. Chronic interaction of chagasic IgG with myocardial mAChRs, behaving as a muscarinic agonist, might lead to cell dysfunction or tissue damage. Also, these antibodies could produce desensitization, internalization or degradation of mAChRs; explaining the progressive blockade of mAChRs in myocardium with parasympathetic denervation, a phenomenon that has been described in the course of Chagas' cardioneuromyopathy.
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PMID:Participation of nitric oxide signaling system in the cardiac muscarinic cholinergic effect of human chagasic IgG. 923 39

We investigated the mechanisms underlying bradykinin (BK)-induced rise in intracellular Ca++ concentration [Ca++]i and insulin secretion using clonal beta cell line RINm5F. Incubation with a range of concentrations of BK increased in concentration-dependent manners both insulin secretion (BK of 10 nM to 10 microM) and [Ca++]i (BK of 100 nM to 100 microM). In Ca++-containing medium, BK (1 microM) induced a biphasic [Ca++]i rise, which was characterized by a Ca++ peak and a sustained Ca++ phase. In the Ca++-free medium, BK failed to increase insulin secretion and induced only a Ca++ peak without the sustained Ca++ phase. Thapsigargin (1 microM), an inhibitor of the Ca++ pump in the endoplasmic reticulum, abolished the Ca++ peak and the sustained phase. Nimodipine (1 microM), a voltage-dependent Ca++ channel blocker, abolished the BK-induced sustained Ca++ phase and inhibited BK-induced insulin release. The BK1 receptor agonist des-Arg9-BK (1 microM) did not change either [Ca++]i or insulin secretion. Both the BK-induced insulin secretion and rise in [Ca++]i were inhibited by a selective BK2 receptor antagonist, HOE 140 (3.3-100 nM), in concentration-dependent manners but were not by a BK1 receptor antagonist des-Arg9,Leu8-BK (1 microM). Pretreatment with pertussis toxin (0.1 microg/ml) did not block the BK-induced insulin secretion or increase in [Ca++]i. U-73122 (4, 6 and 8 microM), a phospholipase C inhibitor, antagonized both the BK-induced insulin secretion and the increase in [Ca++]i in a concentration-dependent and parallel manner. BK increased intracellular concentrations of inositol-1,4,5-trisphosphate (IP3). Neither (p-amylcinnamoyl)anthranilic acid (100 microM), a phospholipase A2 inhibitor, nor N(G)-nitro-L-arginine methylester (100 microM), a nitric oxide synthase inhibitor, inhibited these effects of BK. Taken together, these findings suggested that in beta cells, BK activates BK2 receptors, which, in turn, activate a pertussis toxin-insensitive G protein. The G protein couples to phospholipase C, which promotes the formation of IP3 and diacylglycerol. IP3 releases [Ca++]i from the intracellular Ca++ store, probably the endoplasmic reticulum, which triggers Ca++ influx via voltage-dependent Ca++ channels and thus increases insulin secretion.
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PMID:Mechanisms of bradykinin-induced insulin secretion in clonal beta cell line RINm5F. 931 32

Tunicamycin is a nucleoside antibiotic that inhibits protein glycosylation and palmitoylation. The therapeutic use of tunicamycin is limited in animals because of its toxic effects, particularly in cerebral vasculature. Tunicamycin decreases palmitoylation of the endothelial isoform of nitric oxide synthase, stimulates nitric oxide synthesis, and increases the concentration of intracellular calcium ([Ca2+]i) in bovine aortic endothelial cells (B. J. Buckley and A. R. Whorton. FASEB J. 11: A110, 1997). In the present study, we investigated the mechanism by which tunicamycin alters [Ca2+]i using the Ca2+-sensitive dye fura 2. We found that tunicamycin increased [Ca2+]i without increasing levels of inositol phosphates. When cells were incubated in the absence of extracellular Ca2+, [Ca2+]i rapidly rose in response to tunicamycin, although a full response was not achieved. The pool of intracellular Ca2+ mobilized by tunicamycin overlapped with that mobilized by thapsigargin. Extracellular nickel blocked a full response to tunicamycin when cells were incubated in the presence of extracellular Ca2+. The effects of tunicamycin on [Ca2+]i were partially reversed by washing out the drug, and the remainder of the response was inhibited by removing extracellular Ca2+. These results indicate that tunicamycin mobilizes Ca2+ from intracellular stores in a manner independent of phospholipase C activation and increases the influx of Ca2+ across the plasma membrane.
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PMID:Tunicamycin increases intracellular calcium levels in bovine aortic endothelial cells. 935 74

Our previous studies have shown that inflammatory mediators increase microvascular permeability through a phospholipase C-nitric oxide synthase (NOS)-guanylate cyclase cascade. The aim of this study is to delineate in more detail the signaling pathway leading to microvascular hyperpermeability. Endothelial cytosolic calcium and the apparent permeability coefficient of albumin (Pa) were measured in isolated and perfused coronary venules. Histamine stimulated a rapid increase in cytosolic calcium followed by a transient elevation in Pa. The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) and the guanosine 3',5'-cyclic monophosphate-dependent protein kinase G (PKG) inhibitor KT-5823 abolished the hyperpermeability but did not affect the calcium response to histamine. Similarly, the calcium ionophore ionomycin produced a calcium spike preceding venular hyperpermeability. Blockage of the NOS-PKG cascade inhibited the increase in Pa, whereas the endothelial calcium was still elevated on administration of ionomycin. Furthermore, the relationship between protein kinase C (PKC) and the calcium-NOS-PKG pathway in modulation of venular permeability was investigated. Stimulation of PKC with phorbol 12-myristate 13-acetate (PMA) dramatically increased basal Pa without significantly changing the cytosolic calcium level. The selective PKC inhibitor bisindolylmaleimide abolished the effect of PMA but did not alter the effect of histamines on Pa. In contrast, both L-NMMA and KT-5823 were able to greatly attenuate the increase in Pa caused by PMA. These results suggest that 1) elevation of endothelial cytosolic calcium is an early signaling event preceding nitric oxide (NO) synthesis in the transduction of endothelial hyperpermeability, and 2) activation of PKC may alter the endothelial barrier function partially through the modulation of NO production.
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PMID:Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability. 937 83

Endothelin (ET) is a potent peptide mediator exhibiting a wide variety of effects in both the parenchymal and nonparenchymal hepatic cells. In the Kupffer cell, ET activates several transmembrane signaling pathways to generate numerous second messengers including the phospholipase C-generated products inositol-1,4,5-trisphosphate and diacylglycerol and the cyclooxygenase product prostaglandin E2 via specific ETB-type receptors. In addition to these findings, we have now demonstrated that endothelin stimulates the production of nitric oxide (NO) in the Kupffer cell in a time- and concentration-dependent manner. Western blot analysis indicates that ET-stimulated NO production occurs though activation of the inducible form of the nitric oxide synthase enzyme. These findings have important implications as the stimulation of NO production by ET may be part of the physiological response to inflammation or infection. Elevated levels of ET and NO have been found to be associated with numerous hepatic pathophysiological conditions that may contribute to derangements in the vascular system seen in these conditions.
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PMID:Endothelin-stimulated nitric oxide production in the isolated Kupffer cell. 944 9

Inhibitory G protein activity (Gi) and nitric oxide (NO) modulate muscarinic-cholinergic (MC) inhibition of cardiac beta-adrenergic inotropic responses. We hypothesized that Gi mediates MC-NO synthase (NOS) signal transduction. Isoproterenol (0.2-0.8 microg/min) and acetylcholine (1 microM) were administered to isolated perfused rat hearts pretreated with saline (controls; n = 8) or pertussis toxin (PT; 30 microg/kg intraperitoneally 3 d before study; n = 20). PT abrogated in vitro ADP-ribosylation of Gi protein alpha subunit(s) indicating near-total decrease in Gi protein function. Isoproterenol increased peak +dP/dt in both control (peak isoproterenol effect: +2, 589+/-293 mmHg/s, P < 0.0001) and PT hearts (+3,879+/-474 mmHg/s, P < 0.0001). Acetylcholine reversed isoproterenol inotropy in controls (108+/-21% reduction of +dP/dt response, P = 0.001), but had no effect in PT hearts. In controls, NG-monomethyl-L-arginine (100 microM) reduced basal +dP/dt, augmented isoproterenol +dP/dt (peak effect: +4,634+/-690 mmHg/s, P < 0.0001), and reduced the MC inhibitory effect to 69+/-8% (P < 0.03 vs. baseline). L-arginine (100 M) had no effect in controls but in PT hearts decreased basal +dP/dt by 1, 426+/-456 mmHg/s (P < 0.005), downward-shifted the isoproterenol concentration-effect curve, and produced a small MC inhibitory effect (27+/-4% reduction, P < 0.05). This enhanced response to NO substrate was associated with increased NOS III protein abundance, and a three- to fivefold increase in in vitro calcium-dependent NOS activity. Neomycin (1 microM) inhibition of phospholipase C did not reverse L-arginine enhancement of MC inhibitory effects. These data support a primary role for Gi in MC receptor signal transduction with NOS in rat heart, and demonstrate regulatory linkage between Gi and NOS III protein levels.
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PMID:Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart. 950 85

The mechanism that regulates the synthesis of nitric oxide synthase (NOS), a key enzyme responsible for NO production in the myenteric plexus, remains unknown. We investigated the roles of the vagal nerve and nicotinic synapses in the mediation of NOS synthesis in the gastric myenteric plexus in rats. Truncal vagotomy and administration of hexamethonium significantly reduced nonadrenergic, noncholinergic relaxation, the catalytic activity of NOS, the number of NOS-immunoreactive cells, and the density of NOS-immunoreactive bands and NOS mRNA bands obtained from gastric tissue. These results suggest that NOS expression in the gastric myenteric plexus is controlled by the vagal nerve and nicotinic synapses. We also investigated if stimulation of the nicotinic receptor increases neuronal NOS (nNOS) expression in cultured gastric myenteric ganglia. Incubation of cultured gastric myenteric ganglia with the nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperizinium (DMPP, 10(-10)-10(-7) M), for 24 h significantly increased the number of nNOS-immunoreactive cells and the density of immunoreactive nNOS bands and nNOS mRNA bands. nNOS mRNA expression stimulated by DMPP was antagonized by a protein kinase C antagonist, a phospholipase C inhibitor, and an intracellular Ca2+ chelator. We concluded that activation of the nicotinic receptor stimulates a Ca2+-dependent protein kinase C pathway, which in turn, upregulates nNOS mRNA expression and nNOS synthesis in the gastric myenteric plexus.
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PMID:Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. 952 91

Fluid shear stress enhances NO formation via a Ca2+-independent tyrosine kinase inhibitor-sensitive pathway. In the present study, we investigated the effects of the protein tyrosine phosphatase inhibitor phenylarsine oxide and of fluid shear stress on endothelial NO production as well as on the membrane association and phosphorylation of the NO synthase (NOS) III. Phenylarsine oxide (10 micromol/L) induced an immediate and maintained NO-mediated relaxation of isolated rabbit carotid arteries, which was insensitive to the removal of extracellular Ca2+ and the calmodulin antagonist calmidazolium. This phenylarsine oxide-induced vasodilatation was unaffected by genistein but abrogated by the tyrosine kinase inhibitor erbstatin A. Incubation of native or cultured endothelial cells with phenylarsine oxide resulted in a time-dependent tyrosine phosphorylation of mainly Triton X-100-insoluble (cytoskeletal) proteins, along with a parallel change in the detergent solubility of NOS III, such that the enzyme was recovered in the cytoskeletal fraction. A similar, though slightly delayed, phenomenon was also observed after the application of fluid shear stress but not in response to any receptor-dependent agonist. Although Ca2+-independent NO formation was sensitive to erbstatin A, phenylarsine oxide treatment was associated with the tyrosine dephosphorylation of NOS III rather than its hyperphosphorylation. Proteins that also underwent redistribution in response to the tyrosine phosphatase inhibitor included paxillin, phospholipase C-gamma1, mitogen-activated protein kinase, and the tyrosine kinases Src and Fyn. We envisage that fluid shear stress and tyrosine phosphatase inhibitors may alter the conformation and/or protein coupling of NOS III, facilitating its interaction with specific phospholipids, proteins, and/or protein kinases that enhance/maintain its Ca2+-independent activation.
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PMID:Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. 954 77


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