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)

Thymosin alpha 1 (Talpha1), a 28-amino acid, acidic thymic peptide, is a promising natural biological response modifier (BRM), which augments and regulates the immune network and is thought to be immunostimulatory also. Recently, we have reported the ability of Talpha1 to activate macrophages to tumoricidal state. In the present investigation, the activation of the p42/44 MAP kinase (MAPK)/c-Jun NH2 terminal kinase (JNK) pathway in response to in vitro treatment with Talpha1 in murine bone marrow-derived macrophages (BMDMs) has been demonstrated. The activation and expression of phospho-p42/44 MAPK was dose as well as time dependent with maximum expression occurring at 5-15 min following stimulation with 100 ng/ml of Talpha1. The expression of phospho-p42/44 MAPK was inhibited by the MAPK inhibitor, PD98059, pertussis toxin (PTX), tyrosine kinase inhibitor-genistein and P13K inhibitor-wortmannin. Talpha1-induced BMDM tumoricidal functions like the production of NO and TNF-alpha, the key mediator molecules of macrophage cytotoxicity, were also inhibited by the MAPK inhibitor, PD98059, in a dose-dependent manner. These observations suggest that p42/44 MAPK activation is one of the essential signaling events triggered by Talpha1 and may be responsible for the in vitro activation of BMDMs.
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PMID:Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1. 1178 69

Somatostatin (somatotropin release inhibiting factor, SRIF), exerts its effects via specific G protein coupled receptors of which five subtypes have been cloned (sst1-5). Recently, SRIF receptors have also been cloned from fish tissues. In this study, goldfish sst5 receptors (gfsst5) were expressed and characterised in the Chinese hamster lung fibroblast cell line, that harbours the luciferase reporter gene driven by the serum responsive element (CCL39-SRE-Luci). The agonist radioligands [125I]-LTT-SRIF-28 ([Leu8, DTrp22, 125I-Tyr25]SRIF-28) and [125I][Tyr10]cortistatin-14 labelled similar receptor densities with high affinity and in a saturable manner (pKd: 9.99-9.71; Bmax: 300-350 fmol mg-1). 5'-Guanylyl-imidodiphosphate inhibited radioligand binding to some degree (38.5-57.9%). In competition binding studies, the pharmacological profile of SRIF binding sites defined with [125I]LTT-SRIF-28 and [125I][Tyr10]cortistatin-14 correlated significantly (r2=0.97, n=20). Pharmacological profiles of human and mouse sst5 receptors expressed in CCL39 cells correlated markedly less with those of the gfsst5 profile (r2=0.52-0.78, n > or = b16). Functional expression of the gfsst5 receptor was examined by measurement of agonist-induced luciferase expression and stimulation of [35S]GTPgammaS ([35S]guanosine 5'-O-(3-thiotriphosphate) binding. Profiles were similar to those achieved in radioligand binding studies (r2=0.81-0.93, n=20), although relative potency (pEC50) was reduced compared to pKd values. Relative efficacy profiles of luciferase expression and [35S]GTPgammaS binding, were rather divergent (r2=0.48, n=20) with peptides showing full agonism at one pathway and absence of agonism at the other. BIM 23056 (D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2) acted as an antagonist on the effects of SRIF-14 (pKB=6.74 +/- 0.23) on stimulation of [35S]GTPgammaS binding. Pertussis toxin abolished the effect of SRIF-14 on luciferase expression and [35S]GTPgammaS binding suggesting coupling of the receptor to G(i)/G(o) proteins. In summary, the present studies demonstrate that the gfsst5 receptor has a similar pharmacological profile and transductional properties to mammalian sst5 receptors. The difference in efficacy profiles defined using different functional assays suggests numerous, agonist specific, conformational receptor states, and/or ligand-dependent receptor trafficking.
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PMID:Pharmacological characterisation of the goldfish somatostatin sst5 receptor. 1185 97

Heptahelical opioid receptors utilize Gi proteins to regulate a multitude of effectors including the classical adenylyl cyclases and the more recently discovered mitogen-activated protein kinases (MAPKs). The c-Jun NH2-terminal kinases (JNKs) belong to one of three subgroups of MAPKs. In NG108-15 neuroblastoma x glioma hybrid cells that endogenously express delta-opioid receptors, delta-agonist dose-dependently stimulated JNK activity in a pertussis toxin-sensitive manner. By using COS-7 cells transiently transfected with the cDNAs of delta-opioid receptor and hemagglutinin (HA)-tagged JNK, we delineated the signaling components involved in this pathway. Sequestration of Gbetagamma subunits by transducin suppressed the opioid-induced JNK activity. The possible involvement of the small GTPases was also examined. Expression of dominant negative mutants of Rac and Cdc42 blocked the opioid-induced JNK activation, and a partial inhibition was observed in the presence of the dominant negative mutant of Ras. In contrast, the dominant negative mutant of Rho did not affect the opioid-induced JNK activation. In addition, the receptor-mediated JNK activation was dependent on Src family tyrosine kinases, but independent of phosphatidylinositol-3 kinase and EGF receptor tyrosine kinases. Collectively, these results demonstrate functional regulation of JNK by the delta-opioid receptor, and this pathway requires Gbetagamma, Src kinases and the small GTPases Rac and Cdc42.
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PMID:Rac and Cdc42-dependent regulation of c-Jun N-terminal kinases by the delta-opioid receptor. 1255 70

Classical chemoattractant receptors are of fundamental importance to immune responses. The two major roles of such receptors are the modulation of chemotaxis and the generation of reactive oxygen species. The formyl peptide receptor-like 1 (FPRL1) can be stimulated by two different ligands, Trp-Lys-Tyr-Met-Val-Met-CONH2 (WKYMVM) and lipoxin A4 (LXA4). Although leukocyte chemotaxis mediated by activated FPRL1 has been reported, the role of FPRL1 in superoxide generation remains to be studied. In this study, we examined the effect of WKYMVM or LXA4 on chemotactic migration and superoxide generation in human neutrophils. WKYMVM and LXA4 stimulated neutrophil chemotaxis via tyrosine phosphorylation events. In terms of reactive oxygen species generation, WKYMVM but not LXA4 stimulated superoxide generation in neutrophils. To understand this difference on superoxide generation via the same receptor, FPRL1, we compared the signaling pathways downstream of FPRL1 by the two different ligands. At first, we confirmed that both WKYMVM and LXA4 caused intracellular calcium ([Ca2+]i) increase in a pertussis toxin-sensitive manner and that these ligands competitively inhibited each other with respect to [Ca2+]i increase in neutrophils. This result suggests that WKYMVM and LXA4 share the same receptor, FPRL1. By investigating cellular signaling by WKYMVM and LXA4, we found that WKYMVM but not LXA4 induced extracellular signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinase, and phospholipase A2 (PLA2) activation. We also found that ERK-mediated cytosolic PLA2 activity is essential for superoxide generation. These results indicate that the activation of FPRL1 by the two different ligands can induce differential cellular signaling and unique functional consequences in human neutrophils.
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PMID:Differential signaling of formyl peptide receptor-like 1 by Trp-Lys-Tyr-Met-Val-Met-CONH2 or lipoxin A4 in human neutrophils. 1292 Feb 10

This report describes the cloning and functional annotation of a Caenorhabditis elegans orphan G-protein-coupled receptor (GPCR) (C10C6.2) as a receptor for the FMRFamide-related peptides (FaRPs) encoded on the flp15 precursor gene, leading to the receptor designation FLP15-R. A cDNA encoding C10C6.2 was obtained using PCR techniques, confirmed identical to the Worm-pep-predicted sequence, and cloned into a vector appropriate for eucaryotic expression. A [35S]guanosine 5'-O-(thiotriphosphate) (GTPgammaS) assay with membranes prepared from Chinese hamster ovary (CHO) cells transiently transfected with FLP15-R was used as a read-out for receptor activation. FLP15-R was activated by putative FLP15 peptides, GGPQGPLRF-NH2 (FLP15-1), RGPSGPLRF-NH2 (FLP15-2A), its des-Arg1 counterpart, GPSGPLRF-NH2 (FLP15-2B), and to a lesser extent, by a tobacco hornworm Manduca sexta FaRP, GNSFLRFNH2 (F7G) (potency ranking FLP15-2A > FLP15-1 > FLP15-2B >> F7G). FLP15-R activation was abolished in the transfected cells pretreated with pertussis toxin, suggesting a preferential receptor coupling to Gi/Go proteins. The functional expression of FLP15-R in mammalian cells was temperature-dependent. Either no stimulation or significantly lower ligand-evoked [35S]GTPgammaS binding was observed in membranes prepared from transfected FLP15-R/CHO cells cultured at 37 degrees C. However, a 37 to 28 degrees C temperature shift implemented 24 h post-transfection consistently resulted in an improved activation signal and was essential for detectable functional expression of FLP15-R in CHO cells. To our knowledge, the FLP15 receptor is only the second deorphanized C. elegans neuropeptide GPCR reported to date.
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PMID:Functional annotation of the putative orphan Caenorhabditis elegans G-protein-coupled receptor C10C6.2 as a FLP15 peptide receptor. 1293 67

Activation of the alpha-smooth muscle actin (alpha-SMA) gene during the conversion of fibroblasts into myofibroblasts is an essential feature of various fibrotic conditions. Microvascular compromise and thus local environmental hypoxia are important components of the fibrotic response. The present study was thus undertaken to test the hypothesis that hypoxia can induce transdifferentiation of vascular fibroblasts into myofibroblasts and also to evaluate potential signaling mechanisms governing this process. We found that hypoxia significantly upregulates alpha-SMA protein levels in bovine pulmonary artery adventitial fibroblasts. Increased alpha-SMA expression is controlled at the transcriptional level because the alpha-SMA gene promoter activity, assayed via a luciferase reporter, was markedly increased in transfected fibroblasts exposed to hypoxia. Hypoxic induction of the alpha-SMA gene was mimicked by overexpression of constitutively active Galphai2 (alphai2Q205L) but not Galpha16 (alpha-16Q212L). Blockade of hypoxia-induced alpha-SMA expression with pertussis toxin, a Galphai antagonist, confirmed a role for Galphai in the hypoxia-induced transdifferentiation process. c-Jun NH2-terminal kinase (JNK) inhibitor II and SB202190, but not U0126, also attenuated alpha-SMA expression in hypoxic fibroblasts, suggesting the importance of JNK in the differentiation process. Hypoxia-induced increase in bromodeoxyuridine incorporation, which occurred concomitantly with hypoxia-induced differentiation, was blocked by U0126, suggesting that DNA synthesis and alpha-SMA expression take place through simultaneously activated parallel signaling pathways. Neutralizing antibody against transforming growth factor-beta1 blocked only 30% of the hypoxia-induced alpha-SMA promoter activity. Taken together, our results suggest that hypoxia induces differentiation of vascular fibroblasts into myofibroblasts by upregulating the expression of alpha-SMA, and this increase in alpha-SMA level occurs through Galphai- and JNK-dependent signaling pathways.
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PMID:Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. 1456 89

The mu-opioid receptor (MOR) couples to multiple G proteins, of which coupling to Gs has long been debated. As expected, in opioid naive Chinese hamster ovary cells expressing recombinant MOR, the predominant action of [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) is inhibitory. However, inactivation of Gi/Go proteins via pertussis toxin (PTX) unmasks its ability to facilitate forskolin activation of adenylyl cyclase (AC) activity. Tolerance develops to this effect of DAMGO, which can also be attenuated by cholera toxin (CTX). The latter suggests G mediation. D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), previously considered to be a neutral MOR antagonist, also produces a facilitation of forskolin (FSK) activation of AC that is augmented by chronic morphine. Facilitative effects of CTAP in naive as well as its augmentation in tolerant membranes are both substantially reduced by CTX. This suggests that not only Gs mediation but also G(salpha)-linked signaling is critical to the chronic morphine-induced enhanced facilitative action of CTAP. Interestingly, the (augmented) CTAP facilitation of FSK-stimulated AC activity that is observed in opioid tolerant (but not in naive) membranes is also sensitive to PTX. This can best be explained by postulating the involvement of Gi-derived G(betagamma), which would stimulate type 2 ACs, conditional on the presence of activated G(salpha). The emergence of a G(betagamma) dimension of AC stimulation by CTAP after chronic morphine could explain its ability to augment the stimulatory action of CTAP on AC. These results support putative MOR coupling to Gs and underscore the multifaceted nature and plasticity of MOR G protein coupling.
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PMID:Dual effects of DAMGO [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on adenylyl cyclase activity: implications for mu-opioid receptor Gs coupling. 1499 51

1 Naloxone benzoylhydrazone (NalBzoH) has initially been developed as an agonist of the pharmacologically defined kappa3-opioid receptor and has recently been employed as an antagonist at the opioid receptor-like (ORL1) receptor. In the present study, we investigated the ability of NalBzoH to elicit agonist-like effects on receptor signalling in distinct layers of rat olfactory bulb, a brain region where we have demonstrated the presence of opioid and ORL1 receptors coupled to both stimulation and inhibition of cyclic AMP formation. 2 In membranes of the olfactory nerve-glomerular layer (ON-GL), external plexiform layer (EPL) and granule cell layer (GRL), NalBzoH elicited a concentration-dependent stimulation of guanosine-5'-O-(3-[35S]-thio)triphosphate ([35S]GTPgammaS) binding with pEC50 values ranging from 7.36 to 7.86, whereas the kappa1-opioid receptor agonists (-)-U-50,488 and U-69,593 were inactive. 3 In membranes of GRL, but not ON-GL and EPL, NalBzoH stimulated basal adenylyl cyclase activity by 40% with a pEC50 of 8.14, and significantly potentiated the net enzyme stimulation elicited by corticotropin-releasing hormone and pituitary adenylate cyclase-activating peptide 38. Pertussis toxin prevented the NalBzoH stimulations of [35S]GTPgammaS binding and adenylyl cyclase activity. 4 In membranes of EPL and GRL, but not ON-GL, NalBzoH elicited a concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase activity with pEC50 values of 8.07 and 8.08, respectively. 5 At concentrations that completely blocked the actions of nociceptin/orphanin FQ (N/OFQ), the ORL1 receptor antagonists CompB and [Nphe1]N/OFQ(1-13)NH2 failed to antagonize either the stimulatory or the inhibitory effect of NalBzoH on cyclic AMP formation. Similarly, the kappa1-opioid receptor antagonist nor-binaltorphimine counteracted the NalBzoH effects with relatively low potencies (pKi values=7.67-8.09). 6 Conversely, the selective delta-opioid receptor antagonist TIPP (pKi=9.10) and the selective mu-opioid receptor antagonist CTAP (pKi=8.27) reduced the inhibitory effect of NalBzoH by 70 and 30%, respectively. Moreover, TIPP and CTAP potently inhibited the NalBzoH stimulation of cyclic AMP, each antagonist maximally causing 50% blockade of the agonist response. 7These data demonstrate that in the olfactory bulb NalBzoH activates receptor signalling by acting through delta- and mu-opioid receptors and independently of ORL1 and kappa1-opioid receptors.
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PMID:G protein activation and cyclic AMP modulation by naloxone benzoylhydrazone in distinct layers of rat olfactory bulb. 1545 72

Internalization of cloned rat or human Y4 receptors expressed in Chinese hamster ovary (CHO) cells increased with concentration of all types of Y4 agonists, including human and rat pancreatic polypeptides, the Y1 receptor group co-agonists possessing C-terminal TRPRY.NH2 pentapeptide, and a C-terminally amidated dimeric nonapeptide related to neuropeptide Y, GR231118. These peptides also inhibited forskolin-stimulated adenylyl cyclase activity in Y4 receptor-expressing cells, and stimulated the binding of 35S-labeled GTP-gamma-S to pertussis toxin-sensitive G-proteins in particulates from these cells. Peptide VD-11 (differing from GR231118 only by C-terminal oxymethylation) acted as a competitive antagonist in all of the above processes. Agonist-induced stimulation of the Y4 receptor internalization persisted in the presence of allosteric inhibitors of hPP binding, N5-substituted amilorides, which also were relatively little active in G-protein stimulation and cyclase inhibition by Y4 agonists. Acceleration of Y4 receptor internalization by agonists apparently is related to relaxation of allosteric constraints to ligand attachment and sequestration of the receptor-ligand complex.
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PMID:Internalization of cloned pancreatic polypeptide receptors is accelerated by all types of Y4 agonists. 1621 38

The present study evaluated some of the mechanisms underlying prostaglandin E2 (PGE2)-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE2 (0.10-10.0 nmol/paw) into the hindpaw elicited a dose-related edema formation, with a mean ED50 value of 0.42 nmol/paw. The coinjection of selective E-prostanoid (EP)3 [(2E)-N-[(5-bromo-2-methoxyphenyl)-sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide; L826266), but not EP2 or EP4 (all 10 nmol/paw), receptor antagonists significantly inhibited PGE2-induced paw edema. Like L826266, the PGE2-induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipase C (PLC) inhibitor 1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122). Likewise, the selective neurokinin (NK)1 receptor antagonist N-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenyl-methyl-3-(2-aphthyl)-l-alaninamide (FK888) and the antagonist of vanilloid receptor (TRPV1) receptors 4'-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE2-mediated paw edema. Conversely, the selective NK2, NK3, and calcitonin gene-related peptide (CGRP) CGRP(8-37) receptor antagonists all failed to interfere with PGE2-induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE2-induced paw edema. The inhibitors of protein kinase C (PKC) 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) and mitogen protein-activated kinases (MAPKs; 30 nmol/paw) c-Jun NH2-terminal kinase (JNK) (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125), extracellular signal-regulated kinase (PD98059), and p38 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB203580], but not protein kinase A, markedly decreased the PGE2-mediated edema formation. The i.pl. injection of PGE2 (3 nmol/paw) induced a significant activation of MAPKs, namely, JNK and p38, an effect that was largely prevented by the selective EP3 receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE2 are mediated by EP3 receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK1 receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE2-mediated inflammatory responses in mice.
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PMID:Pharmacological and molecular characterization of the mechanisms involved in prostaglandin E2-induced mouse paw edema. 1664 3


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