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 mechanism of action of the absorption enhancers such as sodium caprate (C10) and decanoylcarnitine (DC) was examined. Both C10 and DC increased the epithelial permeability of fluorescein isothiocyanate dextran 4000 and decreased the transepithelial electrical resistance in Caco-2 cell monolayer. Irrespective of the presence or absence of mucosal calcium, C10 rapidly increased intracellular calcium levels dose-dependently. Compound 48/80, a phospholipase C inhibitor, prevented the increases of the intracellular calcium level and permeability of fluorescein isothiocyanate dextran 4000 by C10. Furthermore, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride, a strong calmodulin inhibitor, also significantly decreased the enhancing effect of C10. These results suggest that C10 releases calcium from intracellular stores via activation of phospholipase C in plasma membrane. The increase of the calcium levels was considered to induce the contraction of calmodulin-dependent actin microfilament, followed by dilatation of the paracellular route. Although DC also increased intracellular calcium levels, neither compound 48/80 nor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride decreased the enhancing effect of DC. The enhancing mechanisms were different for C10 and DC.
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PMID:Absorption-enhancing mechanism of sodium caprate and decanoylcarnitine in Caco-2 cells. 785 88

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
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PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
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PMID:Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. 792 24

Angiotensin II (Ang II) is an important regulator of aldosterone production by bovine adrenal glomerulosa (BAG) cells. Ang II interacts with a specific receptor coupled to a guanyl nucleotide-binding protein (G protein) that controls the activity of phospholipase C. A primary culture of BAG cells was used to study short-term desensitization of the Ang II receptor. After short exposures to Ang II, BAG cells lost some [125I]Ang II binding capacity. This loss was dependent on the duration of the pretreatment and on the concentration of Ang II used. A maximal loss of [125I]Ang II binding of 55 +/- 10% was observed after a pretreatment of 30 min with 30 nM Ang II. The EC50 was 1.3 +/- 0.6 nM (mean +/- SD of three experiments). The desensitization was readily reversible, since most of the binding capacity (higher than 90%) was recovered after a 60-min incubation, at 37 C, in the absence of Ang II. Scatchard studies revealed that the Ang II receptor of BAG cells exists under two affinity states with one dissociation constant of 0.2 nM and another dissociation constant of 1.5 nM. After a 30-min exposure of BAG cells to 10 nM Ang II, an important decrease of high affinity binding sites was observed. The maximal amount of binding sites was similar on control and desensitized cells (around 52,000 receptors per cell). GTP gamma S, a potent activator of G proteins, decreased [125I]Ang II binding to permeabilized BAG cells. This GTP gamma S effect was not observed on permeabilized BAG cells that had previously been desensitized with 10 nM Ang II. These results suggested that, similarly to GTP gamma S, short exposure to 10 nM Ang II caused the uncoupling of Ang II receptor from its G protein. DuP-753 (a selective AT1 angiotensin II type 1 receptor antagonist) markedly unhibited, whereas PD-123319 (a selective AT2 angioten II type 2 receptor antagonist) had no effect on Ang II receptor desensitization, indicating that the AT1 receptor subtype was responsible for the observed phenomenon. Pretreatment of BAG cells with staurosporine (a protein kinase C inhibitor) and R24571 (a calmodulin inhibitor) did not modify Ang II-induced desensitization of AT1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short-term desensitization of the angiotensin II receptor of bovine adrenal glomerulosa cells corresponds to a shift from a high to a low affinity state. 795 36

Previously, we characterized the prostaglandin (PG) F2 alpha receptor linked to phospholipase C activation and DNA synthesis in NIH-3T3 cells (Nakao, A., Watanabe, T., Taniguchi, S., Nakamura, M., Honda, Z-I., Shimizu, T., and Kurokawa, K. (1993) J. Cell. Physiol. 155, 257-264). To elucidate intracellular events evoked via this receptor, we examined changes caused by PGF2 alpha stimulation in the phosphotyrosine composition of cellular proteins. The addition of PGF2 alpha to cells in quiescent culture rapidly increased the levels of phosphotyrosine in cellular proteins with Mr values of 70,000 (pp70), 85,000 (pp85), 92,000 (pp92), 100,000 (pp100), and 125,000 (pp125); the latter was immunologically identified as p125 focal adhesion kinase. The PGF2 alpha-induced changes in the level of intracellular Ca2+ ([Ca2+]i) elevation, formation of inositol phosphates, and [3H]thymidine incorporation followed a similar dose dependence as PGF2 alpha-induced tyrosine phosphorylation. This tyrosine phosphorylation was independent of extracellular Ca2+, while a [Ca2+]i chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (50 microM), completely inhibited the PGF2 alpha-induced elevation of [Ca2+]i, tyrosine phosphorylation, and [3H]thymidine incorporation. Ionomycin (0.1 microM), which induced [Ca2+]i elevation without formation of inositol phosphates, mimicked the PGF2 alpha-induced tyrosine phosphorylation. 12-O-Tetradecanoylphorbol-13-acetate (TPA) also induced [3H]thymidine incorporation in a dose-dependent manner but had no significant effect on tyrosine phosphorylation. The PGF2 alpha-induced tyrosine phosphorylation could be observed even in the cells pretreated with TPA (5 microM, 24 h). PGF2 alpha exhibited an additive effect on TPA-induced [3H]thymidine incorporation but had no effect on the 32P-phosphorylation of a known 80-kDa protein kinase (PK) C substrate. Both staurosporine and H-7 inhibited the PGF2 alpha-induced increase in [3H]thymidine incorporation and tyrosine phosphorylation in a similar dose-dependent manner whether or not cells were pretreated with TPA (5 microM, 24 h). However, W-7 and KN-62 had no effect on these cellular responses even at the concentration for the almost complete inhibition of Ca2+/calmodulin-dependent PKs (20 microM). These results, taken together, indicate that PGF2 alpha receptor-mediated tyrosine phosphorylation is evoked by a [Ca2+]i-dependent mechanism that is sensitive to staurosporine and H-7 but which is independent of PKC or Ca2+/calmodulin PKs. Finally, the data suggest that this PGF2 alpha-induced signaling pathway is linked to the proliferation of cells.
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PMID:Prostaglandin F2 alpha enhances tyrosine phosphorylation and DNA synthesis through phospholipase C-coupled receptor via Ca(2+)-dependent intracellular pathway in NIH-3T3 cells. 802 Dec 71

Addition of glucose to cells of the yeast Saccharomyces cerevisiae causes rapid activation of plasma membrane H(+)-ATPase and a stimulation of cellular H+ extrusion. We show that addition of diacylglycerol and other activators of protein kinase C to intact cells also activates the H(+)-ATPase and causes at the same time a stimulation of H+ extrusion from the cells. Both effects are reversed by addition of staurosporine, a protein kinase C inhibitor. Addition of staurosporine or calmidazolium, an inhibitor of Ca2+/calmodulin-dependent protein kinases, separately, causes a partial inhibition of glucose-induced H(+)-ATPase activation and stimulation of cellular H+ extrusion; together they cause a more potent inhibition. Addition of neomycin, which complexes with phosphatidylinositol 4,5-bisphosphate, or addition of compound 48/80, a phospholipase C inhibitor, also causes near complete inhibition. Diacylglycerol and other protein kinase C activators had no effect on the activity of the K(+)-uptake system and the activity of trehalase and glucose-induced activation of the K(+)-uptake system and trehalase was not inhibited by neomycin, supporting the specificity of the effects observed on the H(+)-ATPase. The results support a model in which glucose-induced activation of H(+)-ATPase is mediated by a phosphatidylinositol-type signaling pathway triggering phosphorylation of the enzyme both by protein kinase C and one or more Ca2+/calmodulin-dependent protein kinases.
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PMID:Possible involvement of a phosphatidylinositol-type signaling pathway in glucose-induced activation of plasma membrane H(+)-ATPase and cellular proton extrusion in the yeast Saccharomyces cerevisiae. 806 Oct 44

MDCK (epithelial cells from the dog kidney) plated at confluence, establish tight junctions in 12-15 hours through a process that requires protein synthesis, formation of a ring of actin filaments in close contact with the lateral membrane of the cells, calmodulin, and a Ca(2+)-dependent exocytic fusion of tight junction (TJ)-associated components. Monolayers incubated in the absence Ca2+ make no TJs. Yet, if Ca2+ is added under these circumstances, TJs are made with a faster kinetics. Ca2+ is needed mainly at a site located on the outer side of the cell membrane, where it activates uvomorulin and triggers the participation of the cellular components mentioned above, via G-proteins associated with phospholipase C and protein kinase C. In principle, the sites of all these molecules and mechanisms involved in junction formation may be where a variety of agents (hormones, drugs, metabolites) act to produce epithelia with a transepithelial electrical resistance (TER) ranging from 10 to 10,000 omega.cm2. This range may be also due to a variety of substances found in serum and in urine, that increase the TER in a reversible and dose-dependent manner.
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PMID:The making of a tight junction. 814 87

The cell activation inhibitor CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[ b]thiophene-2- carboxamide, monosodium salt] was evaluated for its effects on human neutrophil functions. CI-959 inhibited spontaneous migration and chemotaxis toward N-formyl-methionyl-L-leucyl-L-phenylalanine (fMLP) with 50% inhibition (IC50) values of 3.6 and 3.1 microM, respectively. CI-959 also inhibited superoxide anion generation in response to C5a, fMLP, serum-opsonized zymosan (SOZ), concanavalin A (Con A), and calcium ionophore A23187 with IC50 values of 2.5, 4.7, 14.5, 5.4, and 14.8 microM, respectively. In comparison, CI-959 inhibited myeloperoxidase microM, respectively. In comparison, CI-959 inhibited myeloperoxidase release in response to C5a, fMLP, SOZ, and Con A with IC50 values of 11.6, 16.1, 7.5, and < 1.0 microM, respectively, while inhibiting the response to A23187 by only 5.5% at 100 microM. At concentrations up to 100 microM, CI-959 had no effect on the respiratory burst or degranulation in response to L-alpha-1,2-dioctanoylglycerol (DiC8) or phorbol 12-myristate 13-acetate (PMA). In addition, the compound inhibited leukotriene B4 release stimulated by fMLP and SOZ (IC50 values 4.0 and 2.5 microM, respectively), while having less activity against the A23187-stimulated response (IC50 > 100 microM). These results demonstrate that CI-959 inhibits cellular responses to stimuli that mobilize intracellular calcium. For cellular responses to inophore-mediated calcium influx, only oxygen radical production was inhibited by CI-959. CI-959 was further evaluated for its effects on neutrophil stimulus-response coupling. At 100 microM, CI-959 had no effect on human neutrophil phospholipase C or protein kinase C. CI-959 inhibited fMLP-stimulated intracellular calcium mobilization and calcium influx with IC50 values of 16.7 and 3.1 microM, respectively, and exhibited less potent calmodulin antagonist activity (IC50 = 90.5 microM). These results indicate that CI-959 may exert its stimulus- and response-specific inhibitory effects on neutrophil functions, in part, through inhibition of calcium-regulated signalling mechanisms.
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PMID:Selective regulation of human neutrophil functions by the cell activation inhibitor CI-959. 814 14

TRH receptor-related signal transduction mechanism in the pituitary cells and the central nervous system was reviewed. In pituitary cells, TRH binds to its specific receptor on the cell membrane, followed by hydrolysis of inositol phospholipids by activation of phospholipase C leading to an increase in inositol 1,4,5-trisphosphates (IP3) and diacylglycerol (DG). IP3 mobilizes intracellular Ca2+, which activates Ca2+ and Calmodulin dependent protein kinase (Ca-CaM kinase) and DG activates protein kinase C (PKC). Both Ca-CaM kinase and PKC phosphorylates several proteins in the nucleus, plasma membranes, and cytosol resulting in cell responses including hormone secretion and gene expression. Protein dephosphorylation is also involved in TRH action in the pituitary. In the central nervous system, TRH possesses different intracellular signaling systems, which vary with brain regions.
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PMID:[TRH receptor-related signal transduction mechanism]. 819 62

Lower esophageal sphincter (LES) basal tone and contraction in response to maximally effective doses (Emax) of acetylcholine (ACh) may be mediated by different intracellular transduction pathways. In the basal state resting tone, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] formation and levels of diacylglycerol (DAG) (C. Hillemeier, K. N. Bitar, and P. Biancani, unpublished data) are higher in LES circular muscle than in esophageal muscle, which does not maintain tone. In vitro resting tone and spontaneously elevated formation of Ins(1,4,5)P3 in LES circular muscle strips decrease in a dose-dependent manner in response to the phospholipase C antagonist 1-[6-([(17-beta)-3-methoxyestra-1,3, 5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione (U-73122). Basal Ins(1,4,5)P3 formation, however, is submaximal, since it can be increased by cholinergic stimulation. These data suggest that LES tone is associated with partial activation of phospholipase C. We therefore tested submaximal doses of Ins(1,4,5)P3 and DAG in permeabilized LES muscle cells and found that they act synergistically; their interaction depends on calcium release and is mediated through a protein kinase C (PKC)-dependent pathway. In contrast, we have previously shown that contraction induced by Emax of ACh is mediated through calmodulin-dependent mechanisms (14). To investigate these differences, we tested high and low doses of ACh. Contraction induced by high doses of ACh was inhibited by calmodulin but not by PKC antagonists, as previously reported, but low ACh doses were preferentially inhibited by PKC antagonists. Similarly, low Ins(1,4,5)P3 concentrations activated a PKC-dependent pathway, whereas contraction induced by Emax of Ins(1,4,5)P3 was calmodulin dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential signal transduction pathways in cat lower esophageal sphincter tone and response to ACh. 820 23


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