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)

Cross-desensitization among receptors for peptide chemoattractants have been shown to involve two independent processes, receptor phosphorylation and inhibition of phospholipase C (PLC) activation. Receptors for lipid chemoattractants, i.e. platelet activating factor (PAF) and leukotriene B4, did not inhibit the responses of peptide chemoattractant receptors, suggesting distinct signaling pathways. To examine cross-desensitization between receptors for lipid and peptide chemoattractants, cDNA encoding the PAF receptor (PAFR) was co-expressed into RBL-2H3 cells with cDNAs encoding receptors for either formylated peptides (FR), a product of the fifth component of complement (C5aR) or interleukin-8 A (IL-8RA). PAFR was homologously phosphorylated and desensitized by PAF, and cross-phosphorylated and cross-desensitized by fMet-Leu-Phe, C5a, and IL-8. In contrast, the receptors for peptide chemoattractants were neither cross-phosphorylated nor cross-desensitized by PAF. Staurosporine blocked cross-phosphorylation and cross-desensitization of the PAFR by peptide chemoattractants. Truncation of the cytoplasmic tail of PAFR (mPAFR) abolished its homologous and cross-phosphorylation. mPAFR was also resistant to cross-desensitization by peptide chemoattractants at the level of PLC activation. Interestingly, mPAFR mediated a sustained Ca2+ mobilization in response to PAF and was more active in inducing GTPase activity, phosphoinositide hydrolysis, secretion, and phospholipase D activation than the wild type PAFR. In contrast to PAFR, stimulation of the mPAFR cross-phosphorylated and cross-desensitized responses to IL-8RA. As expected, FR, which is resistant to cross-phosphorylation by C5aR and IL-8RA, was not phosphorylated by mPAFR. However, unlike C5aR and IL-8RA, mPAFR did not inhibit the ability of FR to activate PLC. Blocking Ca2+ influx inhibited mPAFR-mediated sustained Ca2+ response, phospholipase D activation and secretion, but not phosphoinositide hydrolysis and cross-phosphorylation and cross-desensitization of IL-8RA. The data herein suggest that cross-desensitization of PAFR by peptide chemoattractants is solely due to receptor phosphorylation. The PAFR and the peptide chemoattractant receptors do not cross-regulate each other at the level of PLC, suggesting distinct regulatory pathways.
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PMID:Cross-desensitization among receptors for platelet activating factor and peptide chemoattractants. Evidence for independent regulatory pathways. 891 May 8

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

Five patients with mild bleeding tendencies characterized by defective thromboxane A2 (TXA2)-induced platelet aggregation are reported. The platelets of all the patients had the ability to bind exogenous TXA2. Bleeding time was markedly prolonged in one patient. In three of the five patients, synthetic TXA2 mimetic (STA2)-induced platelet responses, including IP3 formation, Ca2+ mobilization, phosphatidic acid formation and GTPase activities were selectively defective, suggesting impaired coupling between the TXA2 receptor and phospholipase C activation. However, in the remaining two patients, these responses were all within normal limits. This suggests that the defective site of this type of platelet disorder is heterogenous and that signaling mechanisms other than the TXA2 receptor-phospholipase C pathway are also involved in TXA2-induced platelet aggregation.
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PMID:Pathogenetic analysis of five cases with a platelet disorder characterized by the absence of thromboxane A2 (TXA2)-induced platelet aggregation in spite of normal TXA2 binding activity. 897 34

Thrombin receptor-G protein coupling was investigated in the human epithelial neuroblastoma cell line, SH-EP. In these cells, both alpha-thrombin and thrombin receptor peptides, SFLLRNP (one-letter amino-acid code), which are newly exposed following cleavage by alpha-thrombin, stimulated GTPase activity about 2-fold over basal activity. Pertussis toxin treatment only partially attenuated alpha-thrombin- and SFLLRNP-stimulated GTPase activity by 50%, whereas antibody raised against synthetic heptapeptide SFLLRNP blocked alpha-thrombin-stimulated phosphoinositide hydrolysis more than 80%. Immunoprecipitation studies using this antibody showed that both Gi2, a subtype of guanine nucleotide-binding regulatory proteins (G proteins) mediating inhibition of adenylyl cyclase, and Gq/G11, a G protein mediating stimulation of phospholipase C, were activated by alpha-thrombin. These data suggest that in these cells the thrombin receptor activates pertussis toxin-sensitive and pertussis toxin-insensitive G proteins simultaneously and directly couples to Gi2 and Gq/G11, which mediate different signaling pathways.
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PMID:Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells. 898 57

The Rho family belongs to the Ras-related small GTP-binding protein (G protein) superfamily and regulates various cell functions in which the actomyosin system is involved, including cell morphology, membrane ruffling, cell motility, cell aggregation, cytokinesis, smooth muscle contraction, and yeast budding. Three GDP/GTP exchange proteins (GEPs), named Smg GDS, Dbl, and Rho GDI, and two GTPase activating proteins (GAPs), named Rho GAP and p190 associated with Ras GAP, have been identified. The Rho activity is likely to be regulated by protein kinase C which is linked through phospholipase C to the tyrosine kinase-type membrane receptors and the heterotrimeric G protein-linked receptors. It is likely that both Ras and Rho receive signals from the membrane receptors through different pathways and transduce signals to genes and cytoskeleton, respectively. In carcinogenesis, mutational activation of any component in the Ras signaling pathway may cause abnormal cell proliferation, whereas mutational activation of any component in the Rho signaling pathway may cause invasiveness and metastasis of carcinoma cells.
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PMID:Rho small G protein and cytoskeletal control. 898 86

RGS proteins constitute a newly appreciated and large group of negative regulators of G protein signaling. Four members of the RGS family act as GTPase-activating proteins (GAPs) with apparent specificity for members of the Gi alpha subfamily of G protein subunits. We demonstrate here that two RGS proteins, RGS4 and GAIP, also act as GAPs for Gq alpha, the G alpha protein responsible for activation of phospholipase C beta. Furthermore, these RGS proteins block activation of phospholipase C beta by guanosine 5'-(3-O-thio) triphosphate-Gq alpha. GAP activity does not explain this effect, which apparently results from occlusion of the binding site on G alpha for effector. Inhibitory effects of RGS proteins on G protein-mediated signaling pathways can be demonstrated by simple mixture of RGS4 or GAIP with plasma membranes.
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PMID:RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. 901 99

Thromboxane A2 (TXA2) is a major arachidonic acid metabolite of platelets and induces platelet functions by binding to specific receptors on the membrane. We have found patients with hemostatic defects due to impaired platelet responses to TXA2, and molecular characterization of the patients has been carried out. Platelets from these two unrelated patients showed impaired aggregation responses to TXA2 and its analogues despite the normal response to thrombin. Although the patients' platelets exhibited normal binding activities to TXA2 analogues, they showed decreased GTPase activity and second messenger formation when stimulated by STA2, a stable TXA2 agonist. To understand the molecular basis of this abnormality, we determined the cDNA sequence of the TXA2 receptor by reverse transcription-polymerase chain reaction (RT-PCR) from the patient's platelet RNA, and identified a single amino acid substitution (Arg60 for Leu) in the first cytoplasmic loop of the receptor. This mutation was found in both isoforms of the platelet TXA2 receptor which we have recently found: TXR alpha with the same structure as the placental TXA2 receptor and TXR beta with the same structure as the endothelial TXA2 receptor, and was detected exclusively in affected members of two unrelated families with the disorder. The mutant TXR alpha and TXR beta expressed in COS-m6 cells showed decreased agonist-induced phospholipase C activation despite their normal ligand binding affinities. These results suggest that the Arg60 for Leu mutation is responsible for the disorder and imply a critical role for the first cytoplasmic loop in the interaction of the TXA2 receptor with the G protein.
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PMID:Molecular characterization of a dominantly inherited bleeding disorder with impaired platelet responses to thromboxane A2. 911 32

Recombinant regulators of G protein-signaling (RGS) proteins stimulate hydrolysis of GTP by alpha subunits of the Gi family but have not been reported to regulate other G protein alpha subunits. Expression of recombinant RGS proteins in cultured cells inhibits Gi-mediated hormonal signals probably by acting as GTPase-activating proteins for Galphai subunits. To ask whether an RGS protein can also regulate cellular responses mediated by G proteins in the Gq/11 family, we compared activation of mitogen-activated protein kinase (MAPK) by a Gq/11-coupled receptor, the bombesin receptor (BR), and a Gi-coupled receptor, the D2 dopamine receptor, transiently co-expressed with or without recombinant RGS4 in COS-7 cells. Pertussis toxin, which uncouples Gi from receptors, blocked MAPK activation by the D2 dopamine receptor but not by the BR. Co-expression of RGS4, however, inhibited activation of MAPK by both receptors causing a rightward shift of the concentration-effect curve for both receptor agonists. RGS4 also inhibited BR-stimulated synthesis of inositol phosphates by an effector target of Gq/11, phospholipase C. Moreover, RGS4 inhibited inositol phosphate synthesis activated by addition of AlF4- to cells overexpressing recombinant alphaq, probably by binding to alphaq.GDP.AlF4-. These results demonstrate that RGS4 can regulate Gq/11-mediated cellular signals by competing for effector binding as well as by acting as a GTPase-activating protein.
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PMID:RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis. 911 54

Binding of Endothelin-1 (ET-1) to its heterotrimeric G protein-coupled receptors stimulates various signaling cascades involving the activation of phospholipase C-beta, phospholipase D, protein kinase C (PKC), tyrosine kinases, Ca2+/calmodulin-dependent kinase (CaMKs), and Ras, a small molecular weight G-protein, but, the role of Rho GTPase remains unclear. In this project, we examined whether RhoA contributes to the ET-1-induced signaling cascade to c-fos SRE activation in Rat-2 fibroblast cells. Our results demonstrate that Rho activation is critical for the signal transduction of ET-1 to c-fos SRE.
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PMID:Role of Rho GTPase in the endothelin-1-induced nuclear signaling. 912 36

We describe an 11-year-old girl with a mild bleeding disorder since early childhood. The disorder was characterized by a prolonged bleeding time, and the patient's platelets showed defective aggregation responses to thromboxane A2 (TXA2) mimetic U46619 and arachidonic acid. In contrast, the platelets showed normal responses to thrombin and Ca ionophore A23187. When the platelet TXA2 receptor was examined with the [3H]-labeled TXA2 agonist U46619, the equilibrium dissociation rate constants (kd) and the maximal concentration of binding sites (Bmax) of the patient's platelets were within normal ranges. Normal GTPase activity was also induced in the patient's platelets by stimulation with U46619, however, inositol 1,4,5-triphosphate (IP3) formation was not induced by U46619. These results suggests that the patient's platelets had a defect in phospholipase C activation beyond TXA2 receptors.
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PMID:Defective signal transduction through the thromboxane A2 receptor in a patient with a mild bleeding disorder: deficiency of the inositol 1,4,5-triphosphate formation despite normal G-protein activation. 918 16


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