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)

The allergic mediator release inhibitor 3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo[3,2-b]indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitor of human neutrophil functions in vitro. Over a concentration range from 1 to 100 mumol CI-922 inhibits the chemotactic response of neutrophils to the synthetic chemotaxin N-formyl-methionyl-leucyl-phenylalanine (FMLP). CI-922 also inhibits respiratory and secretory responses of neutrophils in response to agents that stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5, trisphosphate and 1,2 diacylglycerol, including: the plasma membrane receptor-specific ligands FMLP and C5a; serum-opsonized zymosan; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus guanosine-5'-0-(3-thiotriphosphate) (GTP gamma S). CI-922 also inhibits neutrophil functions stimulated by the calcium ionophore A23187. In contrast, CI-922 does not inhibit neutrophil responses to protein kinase C-specific stimuli such as phorbol 12-myristate 13-acetate (PMA) or L-alpha-1,2 dioctanoylglycerol (DiC8). CI-922 also fails to inhibit the synergistic activation of the respiratory burst by suboptimal concentrations of PMA and calcium ionophore A23187. The observation that CI-922 inhibits neutrophil responses to a variety of soluble and particulate stimuli, excluding protein kinase C-specific stimuli, allows us to postulate the site of action of the compound. We propose that CI-922 inhibits neutrophil activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal to phosphorylation reactions mediated by protein kinase C and calmodulin-dependent protein kinases.
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PMID:Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: differential inhibition of responses to a variety of stimuli. 243 26

Monocyte C2 synthesis is stimulated by antigen-antibody complexes (IC), carbamylcholine (C-Ch), phenylephrine (PE) and gamma-interferon. Tetrodotoxin or nifedipine abrogated the effects of IC, C-Ch and PE but did not influence the effect of gamma-interferon on C2 synthesis. Thus stimulation of C2 synthesis by IC, C-Ch and PE is dependent upon activation of Na+/K+ and Ca2+ channels, whereas gamma-interferon operates independently of these ion channels. Calcium channel agonists (CG28392 and BK8644) stimulated C2 synthesis, and this effect was prevented by nifedipine but not by tetrodotoxin. Thus Na+/K+ channels are activated prior to Ca2+ channels. Stimulation of C2 synthesis occurred when phospholipase C or phorbol myristate acetate (PMA) were added to the monocyte cultures, suggesting that PI cycle turnover and protein kinase-C (PK-C) activation are involved in the stimulation of C2 synthesis in monocytes. PMA, an activator of PK-C, stimulated the synthesis of C2, C3, B, P and C1-inhibitor approximately two-fold. In contrast gamma-interferon reduced synthesis of C3 and P by 44% and 22% respectively, and stimulated C1-inhibitor synthesis twelve-fold. These data suggest that the action of gamma-interferon complement synthesis is, at least partially, independent of PK-C activation. The effects of IC, C-Ch, PE, PI, CG28392, BK8644 and gamma-interferon were inhibited by trifluoperazine implying that calmodulin and/or other calcium binding proteins play a role in the modulation of complement protein production.
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PMID:The role of ion channels and protein kinase C activation in the stimulation of complement protein synthesis. 244 31

Important findings on the molecular and regulatory properties of neurotransmitter receptors, GTP-proteins, ion channels and protein kinases were briefly reviewed. On the basis of recent advances in the theme mentioned above, we investigated the transmembrane signalling mechanism of serotonin (5-HT)-evoked inward current responses under the voltage clamp condition (holding at -60mV) in Xenopus oocytes injected with rat brain poly (A)+ mRNA, suggesting that 5-HT evokes a Cl- current via such a mechanism as follows: 1) activation of 5-HT1c subtype of receptors, 2) activation of pertussis toxin-sensitive Gi/G0, 3) phospholipase C activation, 4) inositol 1,4,5-trisphosphate (IP3) formation, 5) an increase of [Ca2+]i liberated by IP3, and 6) gating of Cl channels stimulated perhaps by Ca2+-calmodulin. On the other hand, protein kinase C (C-kinase) activation by diacylglycerol and Ca2+ seems to cause a feedback inhibition to the 5-HT responses by phosphorylation of certain proteins. Voltage-operated Ca channels of the N-type reconstituted in oocytes injected with brain mRNA seem to be modulated by C-kinase as well as by cAMP-dependent protein kinase. Significances of oocytes using as a model system to analyze the molecular mechanism of neuronal signalling in the brain were stressed and reviewed.
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PMID:[Recent advances in molecular pharmacology of cellular signalling mechanism]. 247 36

PGF-2 alpha suppresses the LH-induced accumulation of cyclic AMP in young and mature corpora lutea (CL) of pseudopregnant rats, with mature CL being more sensitive. Calcium ions, and later phospholipase C activation, are believed to mediate this effect. In isolated CL of 2 and 10 days of age, depletion of extracellular calcium, or addition of calmodulin inhibitors or of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate (TMB-8), did not prevent the suppressive effect of PGF-2 alpha. Phorbol 12-myristate 13-acetate augmented, rather than inhibited, the LH-induced cAMP accumulation in young and mature CL. Polyphosphoinositide turnover was stimulated by PGF-2 alpha in young, but not in mature CL. The suppression by PGF-2 alpha of luteal cAMP is therefore apparently not mediated by phospholipase C activation but two phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine and Ro-20-1724, abolished the inhibitory effect of PGF-2 alpha.
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PMID:Mechanism of the luteolytic action of prostaglandin F-2 alpha in the rat. 247 4

The complete nucleotide sequence coding for the chicken brain alpha-spectrin was determined. It comprises the entire coding frame, 5'- and 3'-untranslated sequences terminating in a poly(A)-tail. The deduced amino acid sequence shows that the alpha-chain contains 22 segments, 20 of which correspond to the typical 106 residue repeat of the human erythrocyte spectrin. Some segments non-homologous to the repeat structure reside in the middle and COOH-terminal regions. Sequence comparisons with other proteins show that these segments evidently harbour some structural and functional features such as: homology to alpha-actinin and dystrophin, two typical EF-hand structures (calcium-binding) and a putative calmodulin-binding site in the COOH-terminus and a sequence homologous to various src-tyrosine kinases and to phospholipase C in the middle of the molecule. Comparison of our sequence with other partial alpha-spectrin sequences shows that alpha-spectrin is well conserved in different species and that the human erythrocyte alpha-spectrin is divergent.
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PMID:From the spectrin gene to the assembly of the membrane skeleton. 248 1

The involvement of inositol lipid metabolism in agonist-mediated Ca2+ signaling by Ins 1,4,5-P3 has become firmly established. Recent advances have led to a better understanding of the proteins associated with signal transduction in the plasma membrane. A number of specific receptors (G proteins, phospholipases and inositol lipid kinases) have now been purified and characterized. An Ins 1,4,5-P3 receptor has also been purified which is presumably involved in mediating Ca2+ efflux from intracellular stores. The morphological site of the hormone-sensitive Ca2+ pool has been tentatively identified as discrete, specialized intracellular structures (calciosomes), but further studies are required to demonstrate that these contain Ins 1,4,5-P3-gated Ca2+ channels and their possible functional relationship to the plasma membrane. Receptor occupancy by Ca2+ mobilizing agonists also stimulates Ca2+ entry into the cell, but the mechanism for activation of voltage insensitive Ca2+ channels and the possible involvement of Ins 1,4,5-P3, Ins 1,3,4,5-P4 and/or G proteins in this process has not been established. The Ca2+ signaling pathway is subject to multisite feedback regulation by Ca2+ itself and by a diacylglycerol-mediated activation of protein kinase C. Potential sites for Ca2+ interaction are displacement of Ins 1,4,5-P3 from its receptor by a Ca2+-dependent mechanism, promotion of Ins 1,3,4,5-P4 formation by the Ca2+/calmodulin-regulated Ins 1,4,5-P3 3-kinase, and efflux of Ca2+ from the cell or sequestration into intracellular Ca2+ stores by Ca2+/calmodulin-regulated Ca2+-ATPases. Protein kinase C activation potentially affects the rate of generation of Ins 1,4,5-P3 by negative feedback to the receptor-G protein-phospholipase C transduction system and possibly also the rate of Ins 1,4,5-P3 degradation by activation of an inositol polyphosphate 5-phosphomonoesterase. It may also attenuate the Ca2+ transient directly by increasing the activity of Ca2+-ATPases associated with the plasma membrane and the endoplasmic reticulum. Cell-to-cell heterogeneity in the relative control strengths of these different mechanisms may explain the differences in the Ca2+ signal in different tissues and even in different cells within a population. The ability of Ca2+ and protein kinase C to provide negative feedback at various points in the signal transduction pathway suggests that a complex mechanism involving multiple feedback loops is likely to regulate the generation of Ca2+ oscillations seen in some cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormone effects on cellular Ca2+ fluxes. 249 41

Calcium-mobilizing hormones elicit diverse cellular responses by activating plasma membrane receptors coupled to guanine nucleotide regulatory proteins that promote activation of phospholipase C and hydrolysis of polyphosphoinositides. The cleavage products of phosphatidylinositol bisphosphate, inositol 1,4,5-trisphosphate and diacylglycerol, act as primary signals for calcium mobilization and activation of calmodulin-dependent enzymes and protein kinase C. The metabolism of inositol 1,4,5-trisphosphate to several higher inositol phosphates provides additional compounds with potential regulatory actions on calcium movement and cell responses, and the discovery of multiple isomers of protein kinase C reveals a mechanism for diversification and specificity of hormone action among target cells controlled by the same basic transduction system. In addition to its rapid activation by many hormones and neurotransmitters, the calcium-phospholipid signaling system is utilized by several growth factors and oncogenes, consistent with its pervasive role in the control of both immediate and long-term responses of cells to external messenger molecules.
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PMID:Phosphoinositide metabolism and hormone action. 254 68

Proteins in lacrimal gland fluid are secreted primarily by the acinar cells. Secretory proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, stored in secretory granules, and released upon a change in the cellular level of second messenger. The second messenger level is controlled by a process termed signal transduction. Agonists, primarily neurotransmitters in the lacrimal gland, bind to receptors in the basolateral membrane of secretory cells. This interaction activates enzymes in the membrane that cause production of second messengers. It has been hypothesized that second messengers stimulate secretion by activating specific protein kinases to phosphorylate proteins important for secretion. In the lacrimal gland, cholinergic agonists stimulate protein secretion. They act by activating phospholipase C to break down phosphatidylinositol bisphosphate into 1,4,5-inositol trisphosphate (1,4,5-IP3) and diacylglycerol (DAG). 1,4,5-IP3 causes release of Ca2+ from intracellular stores. This Ca2+, perhaps in conjunction with calmodulin, activates specific protein kinases that may be involved in secretion. DAG activates protein kinase C which stimulates protein secretion. alpha 1-Adrenergic agonists also stimulate lacrimal gland protein secretion. These agonists use a pathway that is separate from that utilized by cholinergic agonists and vasoactive intestinal peptide (VIP). The specific pathway has not been identified but may be DAG and protein kinase C. VIP, beta-adrenergic agonists, alpha-melanocyte stimulating hormone, and adrenocorticotropic hormone are lacrimal gland secretagogues. They activate adenylate cyclase to produce cAMP. cAMP stimulates protein kinase A, which perhaps causes protein secretion. Thus, three separate cellular pathways stimulate lacrimal gland protein secretion. Cholinergic agonists and VIP also stimulate lacrimal gland fluid secretion, and the same signal transduction pathways utilized by these agonists to stimulate protein secretion are most likely used for electrolyte and water secretion.
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PMID:Signal transduction and control of lacrimal gland protein secretion: a review. 254 11

The m1 muscarinic acetylcholine receptor gene was transfected into and stably expressed in A9 L cells. The muscarinic receptor agonist, carbachol, stimulated inositol phosphate generation, arachidonic acid release, and cAMP accumulation in these cells. Carbachol stimulated arachidonic acid and inositol phosphate release with similar potencies, while cAMP generation required a higher concentration. Studies were performed to determine if the carbachol-stimulated cAMP accumulation was due to direct coupling of the m1 muscarinic receptor to adenylate cyclase via a GTP binding protein or mediated by other second messengers. Carbachol failed to stimulate adenylate cyclase activity in A9 L cell membranes, whereas prostaglandin E2 did, suggesting indirect stimulation. The phorbol ester, phorbol 12-myristate 13-acetate (PMA), stimulated arachidonic acid release yet inhibited cAMP accumulation in response to carbachol. PMA also inhibited inositol phosphate release in response to carbachol, suggesting that activation of phospholipase C might be involved in cAMP accumulation. PMA did not inhibit prostaglandin E2-, cholera toxin-, or forskolin-stimulated cAMP accumulation. The phospholipase A2 inhibitor eicosatetraenoic acid and the cyclooxygenase inhibitors indomethacin and naproxen had no effect on carbachol-stimulated cAMP accumulation. Carbachol-stimulated cAMP accumulation was inhibited with TMB-8, an inhibitor of intracellular calcium release, and W7, a calmodulin antagonist. These observations suggest that carbachol-stimulated cAMP accumulation does not occur through direct m1 muscarinic receptor coupling or through the release of arachidonic acid and its metabolites, but is mediated through the activation of phospholipase C. The generation of cytosolic calcium via inositol 1,4,5-trisphosphate and subsequent activation of calmodulin by m1 muscarinic receptor stimulation of phospholipase C appears to generate the accumulation of cAMP.
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PMID:A transfected m1 muscarinic acetylcholine receptor stimulates adenylate cyclase via phosphatidylinositol hydrolysis. 255 56

To evaluate the regulation and effects of pancreatic islet lipoxygenase, adult rat islets were permeabilized, using digitonin or staphylococcal alpha-toxin, and then were studied in a medium simulating an intracellular milieu at fixed ambient concentrations of Ca2+. Permeabilized islets retained 12-lipoxygenase activity, as indicated by conversion of tritiated arachidonic acid to a predominant peak of [3H]12-hydroxyeicosatetraenoic acid (12-HETE); this activity was inhibited (89-98%) by the lipoxygenase blockers nordihydroguaiaretic acid (35 microM), BW755c (250 microM) or ETYA (35 microM). Lesser amounts of compounds coeluting with 15- and 11-HETE (but little or no 5-HETE) were formed; however, 11-HETE (and possibly some 15-HETE) was probably synthesized (at least in part) via cyclooxygenase, as suggested by the partial synthesis blockade induced by 50 microM ibuprofen. The production of 12-HETE did not require the presence of Ca2+, Mg2+ or ATP; it also was not stimulated by addition of cyclic AMP, a phorbol ester, or calmodulin. However, it was augmented modestly by provision of a basal cytosolic free Ca2+ concentration of 60-80 nM, with no further increase at physiologically elevated levels of 260-530 nM. Elevations in cytosolic free Ca2+ concentrations induced insulin release which was inhibited by cooling, epinephrine or protein kinase inhibitors and, therefore, was exocytotic in nature. Lipoxygenase inhibitors blocked this insulinotropic effect of calcium at submaximal or saturating Ca2+ concentrations (with or without its potentiation by 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C) by 53-82%. However, they did not reduce the Ca2+-independent secretory effects (at subnanomolar Ca2+ concentrations) of the phorbol ester alone. Similar results were seen using dibutyryl cyclic AMP to activate protein kinase A. The alpha 2-adrenergic agonists epinephrine or clonidine inhibited Ca2+-, TPA- or cyclic AMP-induced insulin release without reducing HETE formation. We conclude that (1) islet lipoxygenase is constitutively expressed and is not physiologically regulated by alpha 2-adrenergic agonism, Ca2+ or protein kinases; (2) lipoxygenase modulates insulin release; HETE production is not merely an epiphenomenon reflecting the activation (or inhibition) of exocytotic secretion; (3) islet lipoxygenase inhibitors reduce insulin secretion, at least in part, by blocking the direct effects of Ca2+ on exocytosis and/or its synergism with Ca2+-binding proteins such as protein kinase C; and (4) these same inhibitors do not directly poison protein kinase C or A, or the exocytotic apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets. A molecular mechanism distinct from that of alpha 2-adrenergic agonists. 256 95


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