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)

We have studied the effect of gamma-aminobutyric acid (GABA) and other GABA-receptor agonists (3-aminopropanesulphonic acid and muscimol) on the noradrenaline-induced stimulation of polyphosphoinositide metabolism in rat hippocampal slices. Formation of water-soluble inositol phosphates, and polyphosphoinositide metabolism were studied in hippocampal slices prelabelled with [3H]myoinositol. Noradrenaline induced formation of inositol mono-, bis- and trisphosphate during 10 min incubation in the presence of lithium; activation of phospholipase C by noradrenaline was also reflected by the hydrolysis of polyphosphoinositides and by the increased metabolism of phosphatidylinositol. GABA-receptor agonists were unable to activate per se phospholipase C; however, when added together with a low concentration of noradrenaline, they greatly potentiated the noradrenaline-stimulated polyphosphoinositide metabolism. We conclude that GABA-receptor agonists potentiate the effect of noradrenaline on polyphosphoinositide turnover and we discuss the role of this neurotransmitter interaction in the physiology of the hippocampus.
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PMID:Phospholipase C activation induced by noradrenaline in rat hippocampal slices is potentiated by GABA-receptor stimulation. 303 26

The purpose of this study was to investigate the relationship between norepinephrine-induced contraction and hydrolysis of phosphatidylinositols in rat aorta. Norepinephrine-induced contraction was associated with increased accumulation of the hydrolytic products of the phosphatidylinositols, inositol monophosphate and phosphatidic acid. Norepinephrine also induced significant decreases in phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. The alpha-1 adrenoceptor antagonist, prazosin, exposure to the Ca++ channel modulator, nifedipine, and removal of extracellular Ca++ inhibited the accumulation of inositol monophosphate and contraction due to norepinephrine. These results suggest that the contraction induced by norepinephrine may be mediated by processes associated with hydrolysis of phosphatidylinositols. The hydrolysis may occur through Ca++-dependent activation of phospholipase C by alpha-1 adrenoceptor agonists.
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PMID:Effects of norepinephrine on contraction and hydrolysis of phosphatidylinositols in rat aorta. 361 23

Ultrastructural studies of blood cells during the acute stage of the hemolytic-uremic syndrome (HUS) revealed striking, but transient, changes in erythrocyte structure. These included membrane disruption, vacuolar degeneration, and Heinz body formation. There was also evidence of platelet injury, and there were peculiar tactile interactions between histiocytes and impaired red cells. These changes disappeared as the patients recovered. These changes were considered to be important in the pathogenesis of the hemolytic and thrombolytic features of HUS, and studies were directed at reproducing them in vitro and in vivo. Treatment of red cells with purified clostridial phospholipase C induced changes in red cells and platelets that were comparable to those encountered in HUS. Rats infused with phospholipase C developed hemolysis, thrombocytopenia, and hemoglobinuria. Their kidneys did not, however, reveal glomerular alterations similar to those seen in patients with HUS. It is proposed that HUS in some cases might be initiated by a nonspecific infectious injury to the intestinal mucosa thereby allowing increased absorption of toxins derived from indigenous gut flora and that these toxins could be responsible for the hemolysis, thrombolysis, and even the renal injury.
Nephron 1985
PMID:Experimental studies on the hemolytic-uremic syndrome. 397 83

A prototypic Ca(2+)-mobilizing hormone receptor, alpha 1-adrenergic receptor (alpha 1AR), stimulates cAMP accumulation. The mechanism underlying this phenomenon was previously suggested to be secondary to phosphatidylinositol hydrolysis-protein kinase C activation in some cells. We transfected Chinese hamster ovary (CHO)-K1 cells with hamster alpha(1B)AR cDNA and isolated cells stably expressing alpha(1B)AR (CHO alpha 1B cells). We investigated the molecular mechanism underlying the alpha 1AR-mediated cAMP production in the CHO alpha 1B cells. Norepinephrine (NE) stimulated intracellular calcium mobilization and cAMP production through alpha(1B)AR. Pretreatment with a phospholipase C inhibitor, U-73,122 (10 microM), abolished the NE-induced intracellular calcium response, whereas it did not affect the NE-stimulated cAMP production. Treatment with various agents (protein kinase C inhibitors, calcium ionophore, cyclo-oxygenase inhibitor, or pertussis toxin) had little effect on the NE-induced cAMP production. The parent CHO and CHO alpha 1B cells contained similar amounts of Gs alpha (42 and 45 kDa, respectively), as detected with immunoblot analysis, and exhibited similar extents of cAMP synthesis with cholera toxin and forskolin. Adenylyl cyclase activity in the CHO alpha 1B cell membranes was also enhanced by NE. Furthermore, incubation of CHO alpha 1B cell membranes with antiserum directed against the carboxyl-terminal portion of Gs alpha inhibited the NE-stimulated adenylyl cyclase activity. Taken together, the results indicate that the alpha(1B)AR-mediated cAMP synthesis in CHO alpha 1B cells reflects direct stimulation of Gs-adenylyl cyclase. Therefore, the alpha 1AR-stimulated cAMP production observed in some native tissues may involve the multiple mechanisms of the direct activation of Gs-adenylyl cyclase and a secondary effect through activation of phosphatidylinositol hydrolysis.
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PMID:Hamster alpha 1B-adrenergic receptor directly activates Gs in the transfected Chinese hamster ovary cells. 756 18

Previously, we have shown that alpha-2C and alpha-1A adrenergic receptors (AR) stimulate prostacyclin (PGI2) synthesis through a pertussis toxin-sensitive guanine nucleotide-binding protein (G protein) in vascular smooth muscle cells (VSMC). The purpose of this study was to assess the role of Ca++ in PGI2 production elicited by alpha-AR activation and to investigate the modulation of the Ca++ channel by G proteins coupled to these alpha-AR in VSMC. PGI2 was measured as immunoreactive 6-keto-PGF1 alpha by radioimmunoassay and cytosolic calcium ([Ca++]i) by spectrofluorometry using fura-2. Norepinephrine, methoxamine and UK-14304 enhanced 6-keto-PGF1 alpha production and [Ca++]i, which was inhibited by depletion of extracellular Ca++ and by Ca++ channel antagonists (verapamil, nifedipine and PN 200-110). Moreover, the Ca++ channel activator Bay K 8644 increased 6-keto-PGF1 alpha production in a nifedipine-sensitive manner, indicating the involvement of dihydropyridine-sensitive Ca++ channels in VSMC. Pertussis toxin inhibited AR agonist-induced 6-keto-PGF1 alpha production and the increase in [Ca++]i. Alpha AR agonists increase Ca++ influx in the presence of guanosine 5'-0-(2- thiodiphosphate) (GTP-gamma-S), and this effect was blocked in the presence of guanine 5'-O-(2-thiodiphosphate) (GDP-beta-S) and antiserum against Gi alpha 1-2 protein in reversibly permeabilized cells with beta-escin. VSMC of rabbit aortae contain a G protein(s) that was recognized by Gi alpha 1-2 but not Gi alpha 3 or G0 antibodies at 1:200 dilution. The calmodulin inhibitor W-7 blocked AR agonist and Bay K 8644-stimulated 6-keto-PGF1 alpha production. The phospholipase A2 inhibitors 7,7-dimethyleicosadienoic acid and oleoyloxyethyl phosphocholine but not phospholipase C inhibitor U-73122 reduced 6-keto-PGF1 alpha production in VSMC. These data suggest that a pertussis toxin-sensitive G protein, probably Gi alpha 1-2, coupled to alpha AR regulates Ca++ influx, which, in turn, by interacting with calmodulin, increases phospholipase A2 activity to release arachidonic acid for PGI2 synthesis in VSMC of rabbit aortae.
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PMID:Alpha adrenergic receptor subtypes involved in prostaglandin synthesis are coupled to Ca++ channels through a pertussis toxin-sensitive guanine nucleotide-binding protein. 768 1

It is envisaged that circulating IgA complexes play a primary role in the glomerular injury of IgA nephropathy, the most common glomerulonephritis worldwide. In this study, we examined the pathophysiological effects of IgA and IgG isolated from IgA-nephritic patients on the signal transduction of human neutrophils. Heat-aggregated forms and monomers of IgA and IgG were prepared from sera of 11 IgA-nephritic patients and 11 healthy controls. Signal transduction was studied by measuring the inositol triphosphate (IP3) production in neutrophils incubated with the immunoglobulin preparations. Different forms of IgA or IgG from IgA-nephritic patients failed to induce a significant increase in IP3 production directly as compared with control IgA or IgG. However, neutrophils preincubated with heat-aggregated IgA (HAA) from IgA-nephritic patients demonstrated a significant rise in IP3 production upon subsequent stimulation by a chemotactic peptide, FMet-Leu-Phe (FMLP); a similar finding was not observed with heat-aggregated IgG. HAA pretreatment of neutrophils increased FMLP-induced IP3 production in a dose-dependent manner. The raised IP3 production was not due to increased FMLP receptors, as HAA preincubation of neutrophils did not increase the binding of tritiated FMLP. The increased IP3 production upon FMLP stimulation in HAA-primed neutrophils was completely abolished by pertussis toxin in a dose-dependent manner. These findings tend to refute a direct stimulatory effect of HAA on phospholipase C, but, instead, may suggest that HAA prepared from IgA-nephritic patients upregulates the activation of G proteins in the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Nephron 1995
PMID:Heat-aggregated IgA prepared from patients with IgA nephropathy increases priming of human neutrophils to produce inositol triphosphate following FMet-Leu-Phe stimulation in vitro. 789 78

1. Pharmacological characterization of different lysophosphatidylcholines was performed based on their effect on the Ca2+ sensitivity of contraction in alpha-toxin-permeabilized rat mesenteric arteries. Furthermore, the effect of noradrenaline on [3H]-myristate-labelled lysophosphatidylcholine levels was assessed, to investigate whether lysophosphatidylcholines could be second messengers. 2. Palmitoyl or myristoyl L-alpha-lysophosphatidylcholine increased the sensitivity to Ca2+, whereas lysophosphatidylcholines containing other fatty acids had less or no effect. 3. L-alpha-phosphatidylcholine, L-alpha-glycerophosphorylcholine, palmitic acid, myristic acid and choline, potential metabolites of lysophosphatidylcholines, did not affect contractions. 4. Noradrenaline (GTP was required) and GTP gamma S increased the sensitivity to Ca2+, and GDP-beta-S inhibited the effect of noradrenaline. Lysophosphatidylcholines, however, had no requirement for GTP and caused sensitization in the presence of GDP-beta-S. 5. Calphostin C, a relatively specific protein kinase C inhibitor, did not affect contraction induced by Ca2+, but abolished the sensitizing effect of lysophosphatidylcholine. 6. Noradrenaline caused no measurable changes in the levels of [3H]-myristate-labelled phosphatidylcholine and lysophosphatidylcholine at 30 s and 5 min stimulation. 7. These results suggest that lysophosphatidylcholines can increase Ca2+ sensitivity through a G-protein-independent, but a protein kinase C-dependent mechanism. However, the role for lysophosphatidylcholines as messengers causing Ca2+ sensitization during stimulation with noradrenaline remains uncertain because no increase in [3H]-myristate labelled lysophosphatidylcholine could be measured during noradrenaline stimulation.
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PMID:Increase by lysophosphatidylcholines of smooth muscle Ca2+ sensitivity in alpha-toxin-permeabilized small mesenteric artery from the rat. 888 21

1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the non-facilitated release evoked by IS. H-7 also inhibited 0.5 microM PDB-induced facilitation of ACh release but not NA release. 6. Down-regulating PKC by pretreatment for 30 min with 5 microM PDB decreased the facilitated release of ACh and the eserine-induced facilitation of NA release. 7. Electrically evoked contractions of the bladder strips exhibited a biphasic response to PDB (2.5 microM), which consisted of an initial enhancement of the peak amplitude and area followed after 20 min by an inhibition of contractions. H-7 inhibited the electrically evoked contractions in a dose-dependent fashion. 8. It is concluded that a phospholipase C-PKC signal transduction pathway is essential for muscarinic receptor-induced facilitation of ACh and NA release but is not involved in the non-facilitated release of transmitters in the rat urinary bladder.
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PMID:M1 muscarinic receptor-induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C. 891 Feb 12

The present study was undertaken to determine whether extracellular adenosine 5'-triphosphate (ATP) promotes cellular proliferation of cultured rat renal inner medullary collecting duct cells. Extracellular ATP increased inositol 1,4,5-triphosphate (IP3) production and cellular free calcium concentration - [Ca2+]i - in a dose-dependent manner. ATP also caused a transient cellular acidification. Extracellular ATP activated mitogen-activated protein (MAP) kinase and [3H]thymidine incorporation in a dose-dependent manner. However, such effects were not obtained with adenosine 5'-diphosphate, adenosine monophosphate, and adenosine. In addition, uridine triphosphate, a P(2u) purinergic agonist, increased IP3 production and activated MAP kinase. 2-Methylthio ATP, a P(2y) purinergic agonist, also increased IP3 production, but did not affect the MAP kinase activity. We also examined the effect of arginine vasopressin on cellular growth. Arginine vasopressin did not alter MAP kinase activity and [3H]thymidine incorporation in cultured rat renal inner medullary collecting duct cells. These results indicate that extracellular ATP activates phospholipase C mediated through P(2u) and P(2y) purinergic receptors and promotes cellular proliferation mediated through P(2u) purinergic receptors in renal inner medullary collecting duct cells.
Nephron 1997
PMID:Extracellular ATP promotes cellular growth of renal inner medullary collecting duct cells mediated via P2u receptors. 920 Apr 13

1. It has been proposed that protein kinase C (PKC) in sympathetic nerves is activated during action-potential evoked release of noradrenaline and helps maintain transmitter output. We studied this phenomenon further in rat atria radiolabelled with [3H]-noradrenaline. 2. Noradrenaline release was elevated by continuous electrical stimulation of the atria for 10 min at either 5 or 10 Hz. Two inhibitors of PKC, polymyxin B (21 microM) and Ro 318220 (3 microM), markedly inhibited the release of noradrenaline but only at the higher stimulation frequency. 3. Further experiments were conducted with 10 Hz stimulation but for shorter train durations. In this case polymyxin B inhibited noradrenaline release during a 10 or 15 s train of impulses but not during a 5 s train. This suggests that PKC effects are induced during the stimulation train by some process. 4. The diacylglycerol kinase inhibitor R59949 (10 microM), which prevents the breakdown of diacylglycerol, enhanced noradrenaline release elicited by stimulation at 10 Hz for 10 or 15 s. This effect was not seen if polymyxin B was present and suggests that diacylglycerol is the endogenous activator of PKC. 5. The source of the diacylglycerol may be through phospholipase C pathways, since the phospholipase C inhibitor U73122 (3 microM) inhibited noradrenaline release at 10 Hz for 10 s and the effect was not seen if polymyxin B was also present. 6. It is unlikely that phospholipase D is the source of diacylglycerol. Although the phospholipase D inhibitor wortmannin (1 microM) inhibited noradrenaline release, this effect was still observed in the presence of polymyxin B. Furthermore ethanol, which inhibits diacylglycerol formation by phospholipase D, had no effect on noradrenaline release. 7. We therefore suggest that during a train of high frequency pulses phospholipase C is activated and this results in the production of diacylglycerol which in turn activates PKC. This enables the neurones to maintain transmitter release at a high level.
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PMID:Noradrenaline release and the effect of endogenous activation of the phospholipase C/protein kinase C signalling pathway in rat atria. 924 57


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