Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The coupling specificities between muscarinic acetylcholine receptors (porcine M1 and M3 subtypes) and a heterotrimeric GTP binding protein (bovine G01) were examined by analysing receptor-stimulated, phospholipase C (PLC)-mediated chloride current responses in Xenopus oocyte expression system. M1-stimulated responses were suppressed by G01 alpha, and this suppression was reversed by expressing exogenous G beta and G gamma, whereas M3-stimulated responses were enhanced by G01 alpha in the presence or absence of G beta and G gamma. G01 alpha itself, when activated directly by intracellular fluoride injection, efficiently activated PLC and stimulated chloride current responses. The results indicate that M1 receptor does not couple with G01, while M3 receptor activates G01 effectively.
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PMID:Differential selectivity of M1 and M3 type muscarinic acetylcholine receptors in coupling with a G protein G01 alpha examined in Xenopus oocytes. 888 13

The effect of morphine on amylase secretion was studied in isolated rat parotid acinar cells. It was found that aluminum fluoride (AlCl3/NaF) and dibutyryl-cyclic AMP but not by cyclic AMP, enhanced amylase secretion. Cyclic AMP was effective in enhancing secretion following permeabilization of cells with alpha-toxin. Following treatment of cells with alpha-toxin, both GTP and GTP-gamma-S also enhanced secretion. Morphine reduced AlCl3/NaF- or GTP-induced secretion of amylase, but was without effect on GTP-gamma-S-induced secretion. Photoaffinity labeling by the use of [32P] 4-azidoanilido GTP revealed its incorporation into 43 kDa and 31 kDa proteins. Incorporation was further enhanced with AlCl3/NaF. Morphine reduced labeling of the 43 kDa protein. Immunoblot analysis identified the 43 kDa GTP binding protein as Gs. When [gamma 32P] GTP was preloaded into permeabilized acinar cells and its hydrolysis measured, morphine stimulated and AlCl3/NaF inhibited GTPase activity. These results suggested the involvement of Gs in secretion of amylase. Furthermore, morphine reduced secretion of amylase by stimulating GTPase activity and by reducing the incorporation of GTP into Gs.
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PMID:Effect of morphine on secretion of amylase from isolated parotid acini. 893 8

Vasopressin (VP) stimulates pituitary ACTH secretion after binding to V1b VP receptors (V1b-R) coupled to phospholipase C (PLC). This effect of VP on ACTH secretion, unlike that of CRH, is resistant to glucocorticoid feedback. To determine whether changes in V1b-R expression or signaling mediate the refractoriness to glucocorticoids, the effects of glucocorticoids on pituitary VP binding, V1b-R messenger RNA (mRNA) and VP-stimulated inositol phosphate (IP) formation were studied in vivo and in vitro in the rat. Dexamethasone injection for 7 days decreased VP binding but increased V1b-R mRNA, indicating that mRNA levels do not reflect receptor number. In spite of the binding loss, VP-stimulated IP formation was enhanced in dexamethasone-treated rats, suggesting that glucocorticoids increase the coupling efficiency of the V1b receptor to phospholipase C. Pretreatment of pituitary cells in vitro with dexamethasone or corticosterone, also potentiated IP formation by low and high doses of VP, indicating that glucocorticoids act directly in the pituitary and not through changes in hypothalamic factors. The effect is mediated by glucocorticoid receptors because it was blocked by glucocorticoid but not mineralocorticoid antagonists. Dexamethasone potentiated the stimulation of IP by other PLC-dependent ligands (GnRH, TRH) but not that by the calcium ionophore, ionomycin, suggesting a site of action between the receptor and PLC. After treatment with dexamethasone, in vivo or in vitro, Western blot analysis revealed marked increases in the GTP binding protein, Galpha(q), which may account for the potentiating effect of glucocorticoid on ligand-stimulated IP. The data demonstrate that glucocorticoids increase coupling of the V1b-R with PLC thereby providing a mechanism by which VP facilitates corticotroph responsiveness in spite of elevated levels of plasma glucocorticoids during stress.
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PMID:Glucocorticoids increase vasopressin V1b receptor coupling to phospholipase C. 964 96

We previously reported that a novel GTP binding protein (G alpha h) is tissue type transglutaminase (TGII) and transmits the alpha 1B-adrenoceptor (AR) signal to phospholipase C (PLC) through its GTPase function. We have also shown that PLC-delta 1 is the effector in TGII-mediated signaling. In this study, interaction sites on TGII for the alpha 1B-AR were identified using a peptide approach and site-directed mutagenesis, including in vivo reconstitution of TGIIs with the alpha 1B-AR and PLC-delta 1. To identify the interaction sites, 11 synthetic peptides covering approximately 132 amino acid residues of the C-terminal domain of TGII were tested. The studies with the peptides revealed that three peptides, L547-I561, R564-D581, and Q633-E646, disrupted formation of an alpha 1-agonist-alpha 1B-AR-TGII complex and blocked alpha 1B-AR-mediated TGase inhibition in a dose-dependent manner, indicating that these peptide regions are involved in recognition and activation of TGII by the alpha 1B-AR. These three regions were further evaluated with full-length TGIIs by constructing and coexpressing each site-directed mutant with the alpha 1B-AR and PLC-delta 1 in COS-1 cells. Supporting the findings with these peptides, these TGII mutants lost 56-82% the receptor binding ability and reduced by 29-68% the level of alpha 1B-AR-mediated IP3 production via PLC-delta 1 as compared to those with wild-type TGII. The results also revealed that the regions of R564-D581 and Q633-E646 were the high-affinity binding sites of TGII for the receptor and critical for the activation of TGII by the receptor. Taken together, the studies demonstrate that multiple regions of TGII interact with the alpha 1B-AR and that the alpha 1B-AR stimulates PLC-delta 1 via TGII.
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PMID:Alpha 1B-adrenoceptor interacts with multiple sites of transglutaminase II: characteristics of the interaction in binding and activation. 1002 7

The 130-kDa protein was isolated as a novel inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) binding protein from rat brain and was molecularly cloned to be found similar to phospholipase C-delta 1 (Kanematsu, T., Takeya, H., Watanabe, Y., Ozaki, S., Yoshida, M., Koga, T., Iwanaga, S. and Hirata, M., 1992. Putative inositol 1,4,5-trisphosphate binding proteins in rat brain cytosol, J. Biol. Chem. 267, 6518-6525; Kanematsu, T., Misumi, Y., Watanabe, Y., Ozaki, S., Koga, T., Iwanaga, S., Ikehara, Y. and Hirata, M., 1996. A new inositol 1,4,5-trisphosphate binding protein similar to phospholipase C-delta 1, Biochem. J. 313, 319-325). The 130-kDa protein and its deleted protein expressed in COS-1 cells were seen in both the membrane and the cytosol fractions. Truncation of 232 residues from the N-terminus, the protein molecule lacking the pleckstrin homology (PH) domain was also localized in the membrane fraction as much as seen with a full-length protein and other deleted proteins, thereby indicating that the PH domain is not primarily involved in the membrane localization. The addition of Mg2+ to homogenates of COS-1 cells caused the translocation of expressed proteins from the cytosol to the membrane fraction, yet further addition of AlF4- which induced the activation of GTP binding proteins did not cause a further translocation. The protein translocated to the membrane by the addition of Mg2+ was hardly extracted with Triton X-100. The inclusion of Ins(1,4,5)P3 or phosphatidylinositol 4,5-bisphosphate in cell homogenates caused the very small reduction in the amounts of membrane-associated proteins expressed by some constructs. These results indicate that (i) the PH domain is not primarily involved in the membrane localization of the 130-kDa protein, (ii) the activation of GTP binding protein does not appear to cause the translocation of the 130-kDa protein, and (iii) intrinsic phosphatidylinositol 4,5-bisphosphate present in the membrane appears to be involved in the membrane association of the 130-kDa protein to a very small extent, probably through the binding site in the PH domain.
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PMID:Membrane association of a new inositol 1,4,5-trisphosphate binding protein, p130 is not dependent on the pleckstrin homology domain. 1035 26

The response of T-cells to peptide antigen plus major histocompatibility complex (MHC) consists of a series of cellular events collectively called T-cell activation. An essential component of this pathway is phospholipase C (PLC)gamma1, whose hydrolytic activity increases rapidly after binding of ligands to the T-cell receptor (TCR) and consequent activation of tyrosine kinases. Recent studies also suggest a GTP binding protein-dependent activation of PLCbeta during the early steps of T-cell activation. On the basis of these findings, we first checked the expression of PLC isoforms by Western blotting and by confocal and electron microscopy techniques, and then we looked for the phosphoinositide breakdown induced by CD3 engagement in cord and adult T-lymphocytes. Our results indicated that PLCbeta1 was almost exclusively expressed in cord T-cells, whereas PLCbeta2 was more strongly represented in the adult. The amount of PLCgamma1 was found to be larger in the adult than in cord cells. No significant differences were found in PLCgamma2 and delta2 expression. PLCdelta1 was scarcely detectable. On CD3 stimulation, adult lymphocytes gave rise, as expected, to a dramatic increase in phosphoinositide breakdown, whereas in cord cells this response was scarcely detected. These results indicate that a shift in PLC expression occurs in the postnatal period and that this change is associated with induction of the capability to respond to CD3 engagement with phosphoinositide hydrolysis.
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PMID:Immunocytochemical localization of phospholipase C isozymes in cord blood and adult T-lymphocytes. 1037 81

Histamine is present in the epidermis in intracellular and extracellular area and is released from mast cells and keratinocytes in the early stage of inflammation of the skin. Such release may contribute to common itching or intensify the inflammatory responses. Histamine binds to its receptors and participate in regulation of the inflammatory responses by acting on endothelial cells, nerve endings, lymphocytes, monocytes, and leukocytes. Histamine has direct effects on keratinocytes as well. Histamine modulates the proliferation of keratinocytes. The binding of histamine to the receptor on keratinocyte membrane induces activation of adenylate cyclase and phospholipase C through GTP binding protein. We previously reported that histamine induces transient increase in intracellular Ca2+ in cultured normal human epidermal keratinocytes (NHEK) and normal epidermis. H1 and H2 histamine receptors are widely distributed in many tissues and cells. In this study, we investigated which types of histamine receptors are related to the increase in intracellular Ca2+ by histamine stimulation in cultured human epidermal keratinocytes. NHEK were cultured in serum-free KGM medium. With H1 antihistamines, mepyramine and diphenhydramine, histamine responses were moderately but not statistically significantly inhibited. With H2 antihistamine, cimetidine, histamine response was significantly inhibited. Epinephrine response was not affected by these antihistamines. Thus, it is considered that H2 antihistamines specifically block histamine-mediated increase in intracellular Ca2+ of cultured normal human keratinocytes.
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PMID:H2 histamine receptor-mediated increase in intracellular Ca2+ in cultured human keratinocytes. 1051 81

Clostridium perfringens alpha-toxin induces the hemolysis of sheep erythrocytes by activating the metabolism of sphingomyelin (SM) via a GTP binding protein in membranes. alpha-Toxin stimulated the formation of 15-N-nervonoyl sphingosine (C24:1-ceramide), which was identified by positive ion fast atom bombardment-MS and 1H-NMR spectroscopy. C24:1-ceramide stimulated the toxin-induced hemolysis of saponin-pretreated sheep erythrocytes and increased the production of sphingosine 1-phosphate (S1P) in the cells, but N-lignoceroyl sphingosine did not. These events elicited by the toxin in the presence of C24:1-ceramide were significantly attenuated by treatment with dihydrosphingosine, a sphingosine kinase inhibitor. TLC showed that the level of C24:1-ceramide was highest among the ceramides with an unsaturated bond in the fatty acyl chain in the detergent-resistant membranes (DRMs). The toxin specifically bound to DRMs rich in cholesterol, resulting in the hydrolysis of N-nervonoic sphingomyelin (C24:1-SM) in DRMs. Treatment of the cells with pertussis toxin (PT) inhibited the alpha-toxin-induced formation of C24:1-ceramide from C24:1-SM in DRMs and hemolysis, indicating that endogenous sphingomyelinase, which hydrolyzes C24:1-SM to C24:1-ceramide, is controlled by PT-sensitive GTP binding protein in membranes. These results show that the toxin-induced metabolism of C24:1-SM to S1P in DRMs plays an important role in the toxin-induced hemolysis of sheep erythrocytes.
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PMID:The relationship between the metabolism of sphingomyelin species and the hemolysis of sheep erythrocytes induced by Clostridium perfringens alpha-toxin. 1826 51


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