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)

Prostaglandin G/H synthase (PGHS) is one of the key enzymes in prostaglandin synthesis. Regulation of the mRNA expression of the two isozymes PGHS-1 and PGHS-2 was investigated in mesangial cells. PGHS-1 was constitutively expressed and not modulated by any of the stimuli used. PGHS-2 was induced by the platelet products serotonin (5-HT) and thromboxane A2 (used as its analogue U46619), but not by ATP. Expression of PGHS protein was regulated correspondingly; whereas PGHS-1 protein was constitutively expressed, PGHS-2 protein was virtually absent in unstimulated cells, but could increasingly be induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), 5-HT, or fetal calf serum. Induction of PGHS-2 mRNA was transient with a peak after 2-3 h. Stimulated mRNA levels persisted for more than 6 h when transcription was inhibited by actinomycin D or when translation was inhibited by cycloheximide. As shown by specific inhibitors, 5-HT signal transduction was mediated by 5-HT2 receptors, which couple to phospholipase C via pertussis toxin-sensitive G-proteins. Induction of PGHS-2 mRNA by 5-HT was dependent on protein kinase C. Down-regulation of the enzyme by prolonged incubation with TPA abolished 5-HT-induced PGHS-2 mRNA expression. Short time activation of protein kinase C by TPA induced PGHS-2 mRNA expression. On the other hand, TPA given immediately before 5-HT decreased the 5-HT-induced PGHS-2 mRNA expression, indicating a negative feedback. The immunosuppressive drug cyclosporin A reduced induction of PGHS-2 mRNA expression by 5-HT, indicating interference with the signaling cascade, most likely with the Ser/Thr phosphatase calcineurin. Involvement of Tyr phosphorylation in 5-HT signaling was shown by the Tyr kinase inhibitor genistein, which inhibited the induction, while the Tyr phosphatase inhibitor vanadate by itself was able to induce PGHS-2 mRNA expression, which was further augmented when vanadate was combined with 5-HT. PGHS-2 mRNA expression is thus tightly regulated in mesangial cells and therefore allows modulation at various levels by physiological and pharmacological stimuli.
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PMID:Signal transduction pathways responsible for serotonin-mediated prostaglandin G/H synthase expression in rat mesangial cells. 808 94

Several low molecular weight G proteins have been identified, but their functional roles remain unclear. To clarify the involvement of low molecular weight G protein in receptor-stimulated turnover of polyphosphoinositide (PI) turnover, influences of botulinum toxins on serotonin (5-HT)-stimulated Cl- current mediated by PI turnover were investigated using Xenopus oocytes injected with rat brain mRNA. Treatment with botulinum toxin C, D or purified ADP-ribosyltransferase of botulinum toxin (botulinum toxin C3 enzyme) inhibited the 5-HT-induced Cl- current in oocytes, and ADP-ribosylated 23 kDa proteins. Both botulinum toxin C3 enzyme-induced inhibition of the current and ADP-ribosylation were suppressed by pretreatment with antibotulinum toxin C3 enzyme antibody. Botulinum toxin D treatment of oocytes was ineffective in the response of Cl- current induced by injection of 50 pmol inositol 1,4,5-trisphosphate and 50 pmol Ca2+. It is suggested that low molecular weight G proteins ADP-ribosylated by botulinum toxin C3 enzyme are involved in phospholipase C activation in Xenopus oocytes.
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PMID:Inhibitory effects of botulinum toxin on 5-HT1C receptor-induced Cl- current in Xenopus oocytes. 813 79

In this study I attempted to elucidate the depressant effects of volatile anesthetics on inositol trisphosphate (IP3)-mediated signal transduction pathway and to identify the site of action. For this purpose, we used Xenopus laevis oocytes which translated and expressed 5-HT receptors after injection of mRNA isolated from the rat brain. In this system, binding of the agonist to G-protein coupled receptors activates phospholipase C that produces IP3. Mobilization of Ca2+ by IP3 from the storage finally opens Ca2+ dependent Cl- channels. Halothane, isoflurane and methoxyflurane depressed Cl- current elicited by 5-HT. For the further quantitative study, methoxyflurane was used because of its better solubility and less vapor pressure that avoided evaporation of the agent. The 5-HT elicited Cl- current was depressed in a non-competitive fashion. Response were 75, 60, 20% of control in the presence of 0.5, 1 and 3 mM methoxyflurane, respectively. Responses elicited by a pressure-injection of Ca2+ or IP3 remained unchanged in the presence of high concentrations of either halothane, isoflurane or methoxyflurane. These results suggest that the depressant mechanism by volatile anesthetics on the signal transduction pathway involves neither Ca2+ dependent Cl- channel dynamics nor intracellular Ca2+ mobilization by IP3. Changes of microdomain characteristics of the membrane in the presence of anesthetic molecules including membrane-bound proteins and enzyme system may be a main mechanism of action of volatile anesthetics.
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PMID:[Depressant effects of volatile anesthetics on second messenger system in mRNA-expressed Xenopus laevis oocytes]. 815 57

We examined the rate and extent of labeling of total cellular phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol (PI) in canine tracheal smooth muscle in response to maximum levels of two different contractile agonists, carbachol (5.5 microM) and serotonin (5-hydroxytryptamine, 5-HT) (47 microM) and when a second agonist was given during a maximal contraction evoked by the first agonist. Unstimulated tracheal smooth muscle strips were incubated with [3H]-myo-inositol (MI) to label tissue MI without much labeling of inositol phospholipids. With carbachol, there was a 20-fold increase in the [3H]-MI incorporation rate into inositol phospholipids, decreases in PI and PIP2 contents, and increases in phosphatidic acid and diacylglycerol contents. PI and PIP2 specific radioactivities reached plateaus, 0.90 +/- 0.03 and 0.80 +/- 0.04, respectively, compared with [3H]-MI specific radioactivity. 5-HT at 47 microM evoked smaller changes including force development, [3H]-MI incorporation rate and lipid mass changes. However, the plateau of PI and PIP2 labeling reached levels similar to that determined during carbachol-evoked force, 0.90 +/- 0.06 and 0.82 +/- 0.04, respectively. Carbachol (55 microM) addition after incubation with 5-HT did not significantly alter the plateau levels of the specific radioactivities of PI or PIP2, although force and lipid mass changes were significantly changed. We conclude that 5-HT and muscarinic receptor coupling mechanisms utilize the same pool of PIP2 as a substrate for phospholipase C activation and the same PI pool for conversion to PIP and PIP2.
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PMID:Common phosphatidylinositol 4,5-bisphosphate pools are involved in carbachol and serotonin activation of tracheal smooth muscle. 839 64

The Ca2+ channel antagonists nifedipine and verapamil each significantly inhibited (50-100%) the smooth muscle contraction induced in response to either 5-hydroxytryptamine (1 microM, 5-HT) or 20 mM K+ (K(+)-physiological salt solution) in the basilar artery. Simultaneous measurements of smooth muscle membrane potential showed that changes in potential were not modified at this time. A similar inhibitory action against the smooth muscle contraction but not the depolarization to 5-HT was obtained with the putative protein kinase C and phospholipase C inhibitors, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (10 microM, H7) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (70 microM, NCDC). These data indicate that 5-HT-induced Ca2+ influx through voltage sensitive channels is important for smooth muscle contraction but not depolarization in the rabbit basilar artery.
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PMID:Ca2+ channel antagonists and inhibition of protein kinase C each block contraction but not depolarization to 5-hydroxytryptamine in the rabbit basilar artery. 851 72

Serotonin neurons in the rostral and caudal brainstem raphe nuclear groups give rise to collateralized ascending and descending projections which provide modulatory input into most networks throughout the entire neuraxis. The rostral raphe system is interconnected with target forebrain areas through reciprocal limbic-midbrain loops, which suggests that serotonin has a role in the regulation of complex intelligent adaptive behavior. Serotonergic pathways sensitize brainstem and spinal cord central rhythmic pattern generators which organize repetitive autonomic and motor activities, e.g. oral-buccal and nutritive behaviors, facilitate tonically active motor neurons innervating antigravity muscles, and disfacilitate somatosensory information processing. Serotonin effects are mediated by multiple receptor subtypes with distinct pre- and postsynaptic localization and regional distribution pattern. They belong to the G protein superfamily, coupling to adenylate cyclase (5-HT1,4,5,6,7) or phospholipase C (5-HT2), and to the ligand-gated ion channel superfamily (5-HT3). Drugs acting at these receptors are known to modulate various aspects of cooperative social behavior and responding latency, i.e. impulsivity, in a variety of experimental models of anxiety and depression. The clinical efficacy of the so-called selective serotonin reuptake inhibitors (SSRIs) in disorders characterized by poor impulse control, e.g. bulimia nervosa, obsessive-compulsive disorder (OCD) and violent suicidal or homicidal behavior, may likewise be due to improved responding latency.
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PMID:Psychopharmacology of central serotonergic systems. 861 4

The effects of increases in cellular adenosine 3'5'-cyclic monophosphate (cAMP) on 5-hydroxytryptamine-(5-HT-) induced generation of inositol phosphates (IPs) and increases in intracellular Ca2+ ([Ca2+]i) were investigated using canine cultured tracheal smooth muscle cells (TSMCs). Cholera toxin and forskolin induced concentration- and time-dependent cAMP formation with half-maximal effects (-logEC50) produced at concentrations of 7.0 +/- 0.5 and 4.9 +/- 0.4 respectively. Pretreatment of TSMCs with either forskolin or dibutyryl cAMP inhibited 5-HT-stimulated responses. Even after treatment for 24h, these agents still inhibited the 5-HT-induced Ca2+ mobilization. The inhibitory effects of these agents produced both depression of the maximal response and a shift to the right of the concentration response curves of 5-HT. The water-soluble forskolin analogue L-858051 [7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin] significantly inhibited the 5-HT-stimulated accumulation of IPs. In contrast, the addition of 1,9-dideoxy forskolin, an inactive forskolin analogue, had little effect on this response. Moreover, SQ-22536 [9-(tetrahydro-2-furanyl)-9-H-purin-6-amine], an inhibitor of adenylate cyclase, and both H-89 [N-(2-aminoethyl)-5-isoquinolinesulphonamide] and HA-1004[N-(2-guanidinoethyl)-5-isoquinolinesulphonamide], inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit the 5-HT-stimulated accumulation of IPs. These results suggest that activation of cAMP/PKA was involved in these inhibitory effects of forskolin. The AlF4--induced accumulation of IPs was inhibited by forskolin, suggesting that G protein(s) are directly activated by AlF4-- and uncoupled from phospholipase C by forskolin treatment. These results suggest that activation of cAMP/PKA might inhibit the 5-HT-stimulated phosphoinositide breakdown and consequently reduce the [Ca2+]i increase or inhibit both responses independently.
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PMID:Regulation of 5-hydroxytryptamine-induced calcium mobilization by cAMP-elevating agents in cultured canine tracheal smooth muscle cells. 876 73

Hyperreactive responses of asthmatics to bronchoconstrictor agonists are caused by mediators produced by a variety of cell types within the airways. Nerves, mast cells, eosinophils, airway epithelia and airway smooth muscle cells probably all interact to increase bronchomotor tone in response to challenge with allergenic stimuli. In addition to important cell-cell interactions, there may be a significant postjunctional component of airway hyperreactivity in which mediators interact at the level of airway smooth muscle cells. To test this hypothesis, I investigated synergistic interactions of methacholine (MCH), histamine and serotonin using intact and chemically skinned canine tracheal smooth muscle. A threshold concentration of histamine (100 nM) significantly increased force when it was added 20 min after or 10 min before stimulation with low concentrations of MCH (1-10 nM). A threshold concentration of serotonin (10 nM) also significantly increased contractions induced by MCH. Serotonin (10 nM) added during a steady-state contraction induced by 6 or 10 nM MCH increased force and increased fura-2 fluorescence, which suggests that force increases in part because myoplasmic Ca++ increases. I also tested the hypothesis that mechanisms beyond the initial steps of signal transduction contribute to synergism by permeabilizing tracheal smooth muscle fibers with staphylococcal alpha-toxin. Histamine (30 microM), MCH (1 microM), GTP-gamma-S (100 microM) and phorbol dibutyrate (1 microM) all potentiated contractions induced by 1 microM Ca++ in skinned fibers. These data suggest that postjunctional components of airway hyperreactivity may be a combination of synergistic effects of agonists occurring at the level of excitation-contraction coupling as well as sensitization of contractile proteins to Ca++.
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PMID:Agonist synergism in airway smooth muscle contraction. 876 34

The 5-Hydroxytryptamine (5-HT)2C receptor (originally known as the 5-HT1C receptor) is a member of the 5-HT2 subfamily of G protein coupled receptors, which is known to couple to phospholipase C. Within the 5-HT2 subfamily, only the 5-HT2C receptor also coupled to inhibition of forskolin-stimulated cAMP production when expressed at high density (12 pmol/mg membrane protein) in stably transformed AV12 cells. The 5-HT2C receptor coupled with high efficacy to both phospholipase C as measured by IP3 (inositol 1,4,5-trisphosphate) production and to inhibition of forskolin-stimulated cAMP production (EC50 = 2.98 nM +/- 0.9 and IC50 = 47.99 nM +/- 10.25 respectively). The 5-HT2A and 5-HT2B receptors, while coupling to phospholipase C with high affinity (EC50s of 19.24 nM +/- 6.44 and 1.24 nM +/- 0.136 respectively), did not decrease adenylyl cyclase activity. The 5-HT2C receptor actions in both systems showed the expected pharmacology for the 5-HT2C receptor, e.g., mesulergine antagonized the effects of 5-HT and spiperone did not. Preincubation of cells with PTX showed that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even to concentrations as low as 20 ng/ml of PTX. PTX pretreatment of the 5-HT2C bearing cells also unmasked a small stimulatory effect on adenylyl cyclase. When expressed at low density the 5-HT2C receptor potentiated forskolin-stimulated cAMP production by 2 fold while still maintaining its ability to enhance PI hydrolysis. A more modest potentiation of cAMP production was noted with low density expression of the 5-HT2B receptor. Thus the ability of the 5-HT2C receptor to interact with several effectors through at least two different G proteins is, in part, receptor subtype specific but also influenced by receptor density.
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PMID:Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily. 880 27

1. Calcium (Ca2+, 0.1-100 microM) stimulated concentration-dependent contractions in small strips from the rabbit mesenteric artery in which the smooth muscle cells had been permeabilized with Staphylococcus aureus alpha-toxin. 2. 5-Hydroxytryptamine (5-HT) and phenylephrine, each in the presence of 10 microM guanosine 5'-triphosphate (GTP), concentration-dependently stimulated additional contractions in strips sub-maximally contracted by the presence of a buffered concentration of calcium (0.3 microM). All the additional contraction was abolished with the selective inhibitor of protein kinase C, Ro 31-8220 (10 microM). 3. Quinacrine (10-50 microM), an inhibitor of phospholipase A2, selectively inhibited the sensitization to 5-HT, but did not alter the sensitization to either phenylephrine or GTP. 4. Myofilament sensitization to calcium was mimicked by exogenous arachidonic acid (300 microM, in the presence of indomethacin, miconazole and BW755c) and the stable analogue of arachidonic acid, 5,8,11,14-eicosatetrayonic acid (ETYA, 100 microM), and in both cases did not require the additional presence of GTP. Ro 31-8220, but not quinacrine, reduced the sensitization to arachidonic acid by around 30%. 5. These results indicate that G protein-linked myofilament sensitization to calcium in the mesenteric artery that follows the activation of 5-HT receptors, but not alpha 1-receptors, involves phospholipase A2. The sensitization stimulated by each of these different receptors, and a component of the response to arachidonic acid, also appears to involve the activation of protein kinase C.
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PMID:Phospholipase A2 and protein kinase C contribute to myofilament sensitization to 5-HT in the rabbit mesenteric artery. 886 67


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