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

Different forms of phospholipase A2, together with pertussis toxin-sensitive G-proteins, [Ca2+]i (intracellular Ca2+ concentration), protein kinase C, calmodulin, protein tyrosine kinases, mitogen-activated protein kinases and Ca2+/calmodulin-dependent protein kinase appear to play a role in agonist-mediated release of arachidonic acid. Here we report that fibroblasts from 14-day-old mouse embryos with inactivated Gi2alpha (alpha-subunit of the heterotrimeric G-protein Gi2) gene display a marked decrease in the ability of lysophosphatidic acid, thrombin and Ca2+ ionophores to release arachidonic acid compared with their normal counterparts. The requirement for Gi2alpha in the release of arachidonic acid following increased [Ca2+]i may be explained by the incomplete translocation of cytosolic phospholipase A2 observed in Gi2alpha-deficient cells. Paradoxically, inactivation of the Gi2alpha gene resulted in up-regulation of bradykinin receptors and their coupling to increased arachidonic acid release, phospholipase C activity and [Ca2+]i. A concomitant increase in basal phospholipase C activity was also observed in the Gi2alpha-deficient cells. These observations establish a pleiotropic and essential role for Gi2alpha in receptor-phospholipase coupling that contrasts with its less obligatory participation in agonist-mediated inhibition of adenylate cyclase.
 ...
PMID:Agonist-specific alterations in receptor-phospholipase coupling following inactivation of Gi2alpha gene. 957 77

We show that lipopolysaccharide-free actetylated low-density lipoprotein (LDL), but not native LDL, stimulates tumor-necrosis factor-alpha (TNF-alpha) secretion by rat peritoneal macrophages and the signal-transduction pathways involved. The role of the scavenger receptor (SR) in this response was suggested by the absence of an effect induced by native LDL, signal coupling involving pertussis-toxin-dependent guanine-nucleotide-binding regulatory (G) protein, and the complete inhibition of this response by SR ligands [poly(I) and dextran sulfate]. Acetylated LDL induces rapid Ca2+ release from inositol-phosphate-sensitive Ca2+ stores mediated by pertussis-sensitive G proteins and a sustained Ca2+ rise mediated by Ca2+ influx and by Ca2+ release from ryanodine-sensitive Ca2+ stores. Acetylated LDL-induced Ca2+ influx and TNF-alpha production were abolished by inhibitors of phospholipase C (U73122) and phospholipase A2 (bromophenacyl bromide), but were not affected by an inhibitor of protein kinase C (calphostine C). Therefore, Ca2+ influx induced by acetylated LDL is dependent on Ca2+ store depletion. Arachidonate released by acetylated LDL acts as a second messenger to activate TNF-alpha secretion via Ca2+ influx. While the Ca2+ signal was not modified by an inhibitor of protein tyrosine kinases (PTK; herbimycin A), this inhibitor completely blocked TNF-alpha production, suggesting the involvement of PTK downstream of the Ca2+ signal. These results suggest that a sustained elevation of intracellular Ca2+, mediated through Ca2+ influx via the phospholipase-A2-dependent pathway, is essential for induction of TNF-alpha secretion. The type of SR class involved in these pathways remains to be identified.
 ...
PMID:Involvement of calcium and arachidonate metabolism in acetylated-low-density-lipoprotein-stimulated tumor-necrosis-factor-alpha production by rat peritoneal macrophages. 957 94

Polybasic secretagogues such as mastoparan, compound 48/80, substance P, and somatostatin stimulate secretion in rat peritoneal mast cells through direct activation of the heterotrimeric G protein, G(i-3). Cultured RBL-2H3 mast cells do not normally respond to these secretagogues, but, as reported here, they do so after prolonged exposure to the kinase inhibitor, quercetin. This inhibitor, which causes phenotypic changes in RBL-2H3 cells, induces a substantial increase (more than sevenfold) in the expression of alpha subunits of the pertussis toxin-sensitive G proteins, G(i-2) and G(i-3). Compound 48/80-induced secretion is associated with transient hydrolysis of phosphoinositides and a transient increase in cytosolic calcium ions. These responses are inhibited by pertussis toxin, and in addition, secretion is blocked by calcium chelation and the protein kinase C inhibitor, Ro31-7549. These results delineate a pathway for compound 48/80-induced secretion in mast cells via Gi protein(s), phospholipase C, calcium, and protein kinase C. The results also imply that phospholipase C, most likely phospholipase Cbeta3, can be transiently activated in RBL-2H3 cells by subunits of Gi proteins to induce cellular responses.
 ...
PMID:Quercetin sensitizes RBL-2H3 cells to polybasic mast cell secretagogues through increased expression of Gi GTP-binding proteins linked to a phospholipase C signaling pathway. 959 Feb 66

Many Gs-coupled receptors can activate both cAMP and Ca2+ signaling pathways. Three mechanisms for dual activation have been proposed. One is receptor coupling to both Gs and G15 (a Gq class heterotrimeric G protein) to initiate independent signaling cascades that elevate intracellular levels of cAMP and Ca+2, respectively. The other two mechanisms involve cAMP-dependent protein kinase-mediated activation of phospholipase Cbeta either directly or by switching receptor coupling from Gs to Gi. These mechanisms were primarily inferred from studies with transfected cell lines. In native cells we found that two Gs-coupled receptors (the vasoactive intestinal peptide and beta-adrenergic receptors) in pancreatic acinar and submandibular gland duct cells, respectively, evoke a Ca2+ signal by a mechanism involving both Gs and Gi. This inference was based on the inhibitory action of antibodies specific for Galphas, Galphai, and phosphatidylinositol 4,5-bisphosphate, pertussis toxin, RGS4, a fragment of beta-adrenergic receptor kinase and inhibitors of cAMP-dependent protein kinase. By contrast, Ca2+ signaling evoked by Gs-coupled receptor agonists was not blocked by Gq class-specific antibodies and was unaffected in Galpha15 -/- knockout mice. We conclude that sequential activation of Gs and Gi, mediated by cAMP-dependent protein kinase, may represent a general mechanism in native cells for dual stimulation of signaling pathways by Gs-coupled receptors.
 ...
PMID:Alternate coupling of receptors to Gs and Gi in pancreatic and submandibular gland cells. 1036 8

HSG and HT29 cells express muscarinic receptors that increase intracellular free Ca2+ ([Ca2+]i) by activating phospholipase Cbeta. In the present study, we have used the measurement of [Ca2+]i with Fura-2 to show that these receptors are of the M3 sub-type and that the increase in [Ca2+]i triggered when they are activated is not sensitive to pertussis toxin. We have also used replication-deficient adenoviruses expressing wild-type and dominant-negative mutants of the alpha-subunits of the heterotrimeric G proteins, Gq and Gi2, to investigate the mechanisms by which these receptors control phospholipase Cbeta. We find that the Ca2+ response to 100 micromol/l carbachol is not affected by increased expression of the wild-type alpha-subunit of Gq, but is blocked by the dominant-negative mutant of Gq and by both the wild-type and the dominant-negative mutant alpha-subunits of Gi2. Expression of alpha-subunits of Gi2 presumably blocks the response to carbachol by scavenging free betagamma-subunits. We conclude that in HSG and HT29 cells, the Ca2+ response to M3 receptor activation is mediated by the betagamma- rather than the alpha-subunits of Gq.
 ...
PMID:Use of replication-deficient adenoviruses to study signal transduction pathways. Muscarinic responses in HSG and HT29 epithelial cell lines are mediated by G protein betagamma-subunits. 1037 90

The effect of secretory phospholipase A2 (sPLA2) on intracellular Ca2+ signaling in human astrocytoma cells was studied. sPLA2 increased cytosolic [Ca2+] ([Ca2+]c) in both Ca2+-containing and Ca2+-free medium, thus suggesting Ca2+ release from intracellular stores. The activation by sPLA2 of arachidonate release via cytosolic PLA2 (cPLA2) was also independent of extracellular Ca2+. As sPLA2 requires Ca2+ for activity, these results indicate that both Ca2+ mobilization and cPLA2 activation induced by sPLA2 are unrelated to phospholipase activity but dependent on signaling mechanisms. The sPLA2-induced [Ca2+]c peak was sensitive to Bordetella pertussis toxin and inhibited by caffeine, suggesting its mediation by inositol 1,4,5-trisphosphate (IP3). sPLA2 induced tyrosine phosphorylation and membrane targeting of phospholipase Cgamma-1 (PLCgamma-1). Moreover, the Ca2+ peak was sensitive to protein tyrosine kinase inhibitors. sPLA2 activates two signaling pathways: one leading to the activation of the MAP kinase/cPLA2 cascade and another leading to PLCgamma activation and Ca2+ release.
 ...
PMID:Secretory phospholipase A2 induces phospholipase Cgamma-1 activation and Ca2+ mobilization in the human astrocytoma cell line 1321N1 by a mechanism independent of its catalytic activity. 1038 50

Although lysophosphatidylcholine (LPC)-mediated cellular responses are attributed to the activation of protein kinase C (PKC), relatively little is known about the upstream signaling mechanisms that regulate the activation of PKC and downstream mitogen-activated protein (MAP) kinase. LPC activated p42 MAP kinase and PKC in mesangial cells. LPC-mediated MAP kinase activation was inhibited (but not completely) by PKC inhibition, suggesting additional signaling events. LPC stimulated protein tyrosine kinase (PTK) activity and induced Ras-GTP binding. LPC-induced MAP kinase activity was blocked by the PTK inhibitor genistein. Because LPC increased PTK activity, we examined the involvement of phospholipase Cgamma-1 (PLCgamma-1) as a key participant in LPC-induced PKC activation. LPC stimulated the phosphorylation of PLCgamma-1. PTK inhibitors suppressed LPC-induced PKC activity, whereas the same had no effect on phorbol 12-myristate 13-acetate-mediated PKC activity. Other lysophospholipids [e.g., lysophosphatidylinositol and lysophosphatidic acid (LPA)] also induced MAP kinase activity, and only LPA-induced MAP kinase activation was sensitive to pertussis toxin. These results indicate that LPC-mediated PKC activation may be regulated by PTK-dependent activation of PLCgamma-1, and both PKC and PTK-Ras pathways are involved in LPC-mediated downstream MAP kinase activation.
 ...
PMID:Lysophosphatidylcholine activates mesangial cell PKC and MAP kinase by PLCgamma-1 and tyrosine kinase-Ras pathways. 1048 15

If stably expressed in human embryonic kidney (HEK)293 cells, the human Mel(1a)-melatonin receptor activates G(i)-dependent, pertussis toxin-sensitive signaling pathways, i.e., inhibition of adenylyl cyclase and stimulation of phospholipase Cbeta; the latter on condition that G(q) is coactivated. The antagonist luzindole blocks the effects of melatonin and acts as an inverse agonist at the Mel(1a) receptor in both intact cells and isolated membranes. This suggests that the Mel(1a) receptor is endowed with constitutive activity, a finding confirmed on reconstitution of the Mel(1a) receptor with G(i). Because the receptor density is in the physiological range, constitutive activity is not an artifact arising from overexpression of the receptor. In addition, the following findings indicate that the Mel(1a) receptor forms a very tight complex with G(i) which can be observed both in the presence and absence of an agonist. 1) In intact cells and in membranes, high-affinity agonist binding is resistant to the destabilizing effect of guanine nucleotides. 2) The ability to bind an agonist with high affinity is preserved even after exposure of the cells to pertussis toxin, because a fraction of G(i) is inaccessible to the toxin in cells expressing Mel(1a) receptors (but not the A(1)-adenosine receptor, another G(i)-coupled receptor). 3) An antiserum directed against the Mel(1a) receptor coprecipitates G(i) even in the absence of an agonist. We therefore conclude that the Mel(1a) receptor is tightly precoupled and that its constitutive activity may play a role in pacing the biological clock, an action known to involve the melatonin receptors in the suprachiasmatic nucleus.
 ...
PMID:Tight association of the human Mel(1a)-melatonin receptor and G(i): precoupling and constitutive activity. 1053 8

Galpha15 activates phospholipase Cbeta in response to the greatest variety of agonist-stimulated heptahelical receptors among the four Gq class G-protein alpha subunits expressed in mammals. Galpha15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the Galpha15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in Galpha15(-/-) mice, Galpha15(-/-) Galphaq(-/-) double-knockout mice (which express only Galpha11 in most hematopoietic cells), and Galpha11(-/-) mice, suggesting functional redundancy in Gq class signaling. Inflammatory challenges, including thioglycolate-induced peritonitis and infection with Trichinella spiralis, stimulated similar responses in Galpha15(-/-) adults and wild-type siblings. Agonist-stimulated Ca(2+) release from intracellular stores was assayed to identify signaling defects in primary cultures of thioglycolate-elicited macrophages isolated from Galpha15(-/-) mice. C5a-stimulated phosphoinositide accumulation and Ca(2+) release was significantly reduced in Galpha15(-/-) macrophages. Ca(2+) signaling was abolished only in mutant cells pretreated with pertussis toxin, suggesting that the C5a receptor couples to both Galpha15 and Galphai in vivo. Signaling evoked by other receptors coupled by Gq class alpha subunits appeared normal in Galpha15(-/-) macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class alpha subunits may suppress abnormalities in Galpha15-deficient mice.
 ...
PMID:Normal hematopoiesis and inflammatory responses despite discrete signaling defects in Galpha15 knockout mice. 1062 36

In the complex signal transduction networks involving G protein-coupled receptors there are numerous examples where G(i)-linked receptors augment G(q)-dependent signals. The mechanistic basis of such occurrences is thought to entail signal convergence at phospholipase Cbeta (PLCbeta) via the G protein betagamma-dimers. Herein, we explored the possibility that augmentation by betagamma-dimers requires preactivation of PLCbeta. COS-7 cells were transiently cotransfected with cDNAs encoding various combinations of receptors and G protein subunits. The G(i)-coupled delta- and kappa-opioid receptors could not stimulate PLCbeta unless they were coexpressed with Galpha(16). The opioid-induced response was dose-dependent and partially inhibited by pertussis toxin or coexpression with transducin, indicating the involvement of betagamma-subunits released from the G(i) proteins. When PLCbeta was preactivated by constitutively active mutants of Galpha(16), Galpha(q), or Galpha(14), opioids enhanced the activity by 80 to 300% and such responses were mostly pertussis toxin-sensitive. The opioid-induced enhancement was dose-dependent and could not be blocked by staurosporin, a protein kinase C inhibitor. Other G(i)-coupled receptors that were ineffective on their own also acquired the ability to stimulate PLCbeta in the presence of a constitutively active mutant of Galpha(q). Coactivation of endogenous or exogenous G(q)-coupled receptors with the delta-opioid receptor produced strong stimulations of PLCbeta and such responses could be partially blocked by pertussis toxin. These results show that enhancement of G(q)-dependent signals by G(i)-coupled receptors requires activated PLCbeta and is mediated via the betagamma-dimer.
 ...
PMID:Preactivation permits subsequent stimulation of phospholipase C by G(i)-coupled receptors. 1072 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>