Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular sphingosylphosphorylcholine (SPC) and galactosylsphingosine (psychosine) induced Ca2+ mobilization in a dose-dependent manner in HL60 leukemia cells. The rapid and transient increase in intracellular Ca2+ concentration ([Ca2+]i) elicited by SPC and psychosine at concentrations lower than 30 microM was inhibited by treatment of the cells with pertussis toxin (PTX) and U73122, a phospholipase C inhibitor, as was the case for UTP, a P2-purinergic agonist. The increase in [Ca2+]i induced by these lysosphingolipids was associated with inositol phosphate production, which was also sensitive to PTX and U73122. The inositol phosphate response is not secondary to the increase in [Ca2+]i as evidenced by the observation that thapsigargin and ionomycin, Ca2+ mobilizing agents, never induced inositol phosphate production and, unlike lysosphingolipids, the [Ca2+]i rise by these agents was totally insensitive to PTX and U73122. When HL60 cells were differentiated into neutrophil-like cells by dibutyryl cyclic AMP, inositol phosphate and Ca2+ responses to AlF4- were enhanced, probably reflecting an increase in the amount of Gi2 and Gi3 compared with undifferentiated cells. In the neutrophil-like cells, however, the responses to SPC and psychosine were markedly attenuated. This may exclude the possibility that the lysosphingolipids activate rather directly PTX-sensitive GTP-binding proteins or the phospholipase C itself. Other lysosphingolipids including glucosylsphingosine (glucopsychosine) and sphingosylgalactosyl sulfate (lysosulfatides) at 30 microM or lower concentrations also showed PTX- and U73122-sensitive Ca2+ mobilization and inositol phosphate response in a way similar to SPC and psychosine. However, platelet-activating factor and lysoglycerophospholipids such as lysophosphatidylcholine and lysophosphatidic acid were less effective than these lysosphingolipids in the induction of Ca2+ mobilization. Taken together, the results indicate that a group of lysosphingolipids at appropriate doses induces Ca2+ mobilization through inositol phosphate production by phospholipase C activation. The lysosphingolipids-induced enzyme activation may be mediated by PTX-sensitive GTP-binding protein-coupled receptors, which may be different from previously identified platelet-activating factor receptor or lysophosphatidic acid receptor.
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PMID:Pertussis toxin inhibits phospholipase C activation and Ca2+ mobilization by sphingosylphosphorylcholine and galactosylsphingosine in HL60 leukemia cells. Implications of GTP-binding protein-coupled receptors for lysosphingolipids. 759 44

Identification of a new family of proteins (RGS proteins) that function as negative regulators of G protein signaling has sparked new understanding of desensitization of this signaling process. Recent studies with several mammalian RGS proteins has delineated their ability to interact with and function as GTPase-activating proteins specifically for G proteins in the Gi family. Here, we investigated the functional activity of RGS3 and a truncated form of RGS3 on G protein-coupled receptor-mediated activation of adenylyl cyclase, phosphoinositide phospholipase C, and mitogen-activated protein kinase in intact cells. Polymerase chain reaction and 5'-rapid amplification of cDNA ends analyses revealed the tissue-specific expression of a short form of the RGS3 transcript that encodes the approximate carboxyl-terminal half of RGS3. This truncated form of RGS3 (RGS3T) was shown recently to function as a negative regulator of pheromone signaling in yeast (Druey, K. M., Blumer, K. J., Kang, V. R., and Kehrl, J. H. (1996) Nature 379, 742-746). Baby hamster kidney cells transiently transfected with RGS3T cDNA exhibited a pronounced impairment in platelet-activating factor receptor-stimulated inositol phosphate production, a pertussis toxin-insensitive response. Similarly, calcitonin gene-related peptide receptor-stimulated increases in intracellular cAMP and pituitary adenylate-cyclase activating polypeptide receptor-stimulated increases in both cAMP and inositol phosphates were reduced significantly in RGS3T transfectants compared with vector-transfected control cells. In contrast, baby hamster kidney cells transfected with the full-length RGS3 cDNA showed no impairment in cAMP and inositol phosphate production mediated by these G protein-coupled receptors. However, lysophosphatidic acid receptor-stimulated phosphorylation of endogenous ERK1 and ERK2 was impaired markedly in both RGS3 and RGS3T transfectants, demonstrating the functional ability of both RGS forms to modulate Gi-mediated signaling. These results provide the first evidence for regulatory effects of an RGS protein on Gs- and Gq-mediated signaling in intact cells and document that the carboxyl-terminal region of RGS3 comprises the structural domain for this activity.
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PMID:A truncated form of RGS3 negatively regulates G protein-coupled receptor stimulation of adenylyl cyclase and phosphoinositide phospholipase C. 918 81

The recent identification of the Vzg-1/Edg2 protein as a functional G protein-coupled receptor for lysophosphatidic acid (LPA) has allowed a sequence-based search for new genes that may encode novel subtypes of LPA receptors. A human cDNA encoding a G protein-coupled receptor, designated Edg4, was identified by searching the GenBankTM for homologs of the human Edg2 LPA receptor. The Edg4 protein is 46% identical and 72% similar in amino acid sequence to human Edg2. When overexpressed in Jurkat T cells, the Edg4 protein mediated LPA-induced activation of a serum response element reporter gene with LPA concentration dependence (EC50 of 10 nM) and specificity. This LPA-induced reporter gene activation could be partially inhibited by pretreatment with pertussis toxin or C3 exoenzyme, suggesting requirements for both a Gi protein and Rho GTPase. Overexpression of Edg4 in Jurkat cells also led to increases in specific binding sites for [3H]LPA. Northern blots revealed that two edg4 mRNA transcripts of 1.8 and 8 kilobases are distributed very differently from edg2 mRNAs in adult human tissues and several cancer cell lines. The existence and distinctive tissue expression of structurally different subtypes of LPA receptors may provide one basis for tissue-specific functions and permit independent regulation of each subtype of LPA receptor.
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PMID:Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. 952 86

Lysophosphatidic acid (LPA) is a bioactive molecule involved in inflammation, immunity, wound healing, and neoplasia. Its pleiotropic actions arise presumably by interaction with their cell surface G protein-coupled receptors. Herein, the presence of the specific nuclear lysophosphatidic acid receptor-1 (LPA1R) was revealed in unstimulated porcine cerebral microvascular endothelial cells (pCMVECs), LPA1R stably transfected HTC4 rat hepatoma cells, and rat liver tissue using complementary approaches, including radioligand binding experiments, electron- and cryomicroscopy, cell fractionation, and immunoblotting with three distinct antibodies. Coimmunoprecipitation studies in enriched plasmalemmal fractions of unstimulated pCMVEC showed that LPA1Rs are dually sequestrated in caveolin-1 and clathrin subcompartments, whereas in nuclear fractions LPA1R appeared primarily in caveolae. Immunofluorescent assays using a cell-free isolated nuclear system confirmed LPA1R and caveolin-1 co-localization. In pCMVEC, LPA-stimulated increases in cyclooxygenase-2 and inducible nitric-oxide synthase RNA and protein expression were insensitive to caveolea-disrupting agents but sensitive to LPA-generating phospholipase A2 enzyme and tyrosine kinase inhibitors. Moreover, LPA-induced increases in Ca2+ transients and/or iNOS expression in highly purified rat liver nuclei were prevented by pertussis toxin, phosphoinositide 3-kinase/Akt inhibitor wortmannin and Ca2+ chelator and channel blockers EGTA and SK&F96365, respectively. This study describes for the first time the nucleus as a potential organelle for LPA intracrine signaling in the regulation of pro-inflammatory gene expression.
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PMID:Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. 1284 11

Lysophosphatidylserine (LPS) may be generated after phosphatidylserine-specific phospholipase A2 activation. However, the effects of LPS on cellular activities and the identities of its target molecules have not been fully elucidated. In this study, we observed that LPS stimulates an intracellular calcium increase in L2071 mouse fibroblast cells, and that this increase was inhibited by 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122) but not by pertussis toxin, suggesting that LPS stimulates calcium signaling via G-protein coupled receptor-mediated phospholipase C activation. Moreover, LPS-induced calcium mobilization was not inhibited by the lysophosphatidic acid receptor antagonist, (S)-phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl} ester (VPC 32183), thus indicating that LPS binds to a receptor other than lysophosphatidic acid receptors. It was also found that LPS stimulates two types of mitogen-activated protein kinase [i.e., extracellular signal-regulated protein kinase (ERK) and p38 kinase] in L2071 cells. Furthermore, these LPS-induced ERK and p38 kinase activations were inhibited by pertussis toxin, which suggests the role of pertussis toxin-sensitive G-proteins in the process. In terms of functional issues, LPS stimulated L2071 cell chemotactic migration, which was completely inhibited by pertussis toxin, indicating the involvement of pertussis toxin-sensitive G(i) protein(s). This chemotaxis of L2071 cells induced by LPS was also dramatically inhibited by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and by 2'-amino-3'-methoxyflavone (PD98059). This study demonstrates that LPS stimulates at least two different signaling cascades, one of which involves a pertussis toxin-insensitive but phospholipase C-dependent intracellular calcium increase, and the other involves a pertussis toxin-sensitive chemotactic migration mediated by phosphoinositide 3-kinase and ERK.
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PMID:Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. 1636 94

In this study, we observed that lysophosphatidylglycerol (LPG) stimulates extracellular signal-regulated kinase (ERK) in human umbilical vein endothelial cells (HUVECs). LPG-stimulated ERK activity was not inhibited by pertussis toxin (PTX), indicating PTX-sensitive G-proteins-independent manner. In terms of functional aspect, LPG induced chemotactic migration of HUVECs in a PTX-insensitive manner. Preincubation of HUVECs with an ERK inhibitor (PD98059) completely inhibited LPG-induced chemotactic migration, suggesting the crucial role of ERK in the process. LPG-induced ERK activation and chemotactic migration in HUVECs were not affected by an lysophosphatidic acid receptor-selective antagonist (Ki16425), indicating lysophosphatidic acid receptors-independency. We also found that LPG stimulated tube formation in HUVECs. Taken together we suggest that LPG stimulates HUVECs and result in chemotactic migration and tube formation, suggesting a new aspect of LPG as a modulator of endothelial cell functioning.
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PMID:Lysophosphatidylglycerol stimulates chemotactic migration and tube formation in human umbilical vein endothelial cells. 1788 75