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)

Direct hyperalgesia induced by prostaglandin E2 (PGE2) can be blocked by mu- but not delta- or kappa-opioids. However, there is evidence that kappa- and delta-opioid receptors are located on sympathetic postganglionic neuron (SPGN) terminals, which mediate bradykinin (BK) hyperalgesia via SPGN-terminal-dependent production of PGE2. Therefore, we evaluated the antinociceptive effect of delta- and kappa-opioids on BK hyperalgesia. We demonstrate that the mechanical hyperalgesia induced by intradermal injection of BK can be blocked by the kappa-opioid agonist trans-3,4-dichloro-N-methyl-N[2-(-pyrrolidinyl)cyclo-hexyl] benzeneacetamide (U50,488H) and by the delta-opioid agonist (D-Pen2,5)-enkephalin (DPDPE), as well as the mu-opioid agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol(DAMGO). Pertussis toxin prevented the inhibition of BK-induced hyperalgesia by U50,488H, DPDPE, or DAMGO. We conclude that the observed peripheral analgesic effects of kappa- and delta-opioid agonists result from actions upon SPGN terminals and that these effects are mediated by inhibitory G-proteins.
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PMID:Kappa- and delta-opioids block sympathetically dependent hyperalgesia. 201 Aug 15

The adherence of Bordetella pertussis to human respiratory cilia is critical to the pathogenesis of whooping cough but the significance of bacterial attachment to macrophages has not been determined. Adherence to cilia and macrophages is mediated by two large, nonfimbrial bacterial proteins, filamentous hemagglutinin (FHA), and pertussis toxin (PT). PT and FHA both recognize carbohydrates on cilia and macrophages; FHA also contains an Arg-Gly-Asp (RGD) sequence which promotes bacterial association with the macrophage integrin complement receptor 3 (CR3). We determined that virulent B. pertussis enter and survive in mammalian macrophages in vitro and that CR3 is important for this uptake process. We then determined the relative contribution of CR3 versus carbohydrate-dependent interactions to in vivo pulmonary colonization using a rabbit model. B. pertussis colonized the lung as two approximately equal populations, one extracellular population attached to ciliary and macrophage surface glycoconjugates and another population within pulmonary macrophages. Loss of the CR3 interaction, either by mutation of FHA or treatment with antibody to CR3, disrupted accumulation of viable intracellular bacteria but did not prevent lung pathology. In contrast, elimination of carbohydrate-bound bacteria, either by a competitive receptor analogue or an anti-receptor antibody, was sufficient to prevent pulmonary edema. We propose that CR3-dependent localization of B. pertussis within macrophages promotes persistence of bacteria in the lung without pulmonary injury. On the other hand, the presence of extracellular bacteria adherent to cilia and macrophages in carbohydrate-dependent interactions is associated with pulmonary pathology.
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PMID:Integrin-mediated localization of Bordetella pertussis within macrophages: role in pulmonary colonization. 202 24

The gene prn encoding the outer-membrane protein P.70 (pertactin) from Bordetella parapertussis has been cloned in Escherichia coli and its DNA sequence determined. Analysis of the DNA sequence reveals that the gene has an open reading frame comprising 922 amino acids capable of encoding a protein with a molecular weight of 95,177 (P.95). In vivo processing of this precursor yields a protein with an estimated Mr of 70 kDa (P.70) which is located on the surface of B. parapertussis. Homology between the prn gene from B. parapertussis and that from Bordetella pertussis is 91.3%. The homology is 93% when the protein sequence of P.95 is aligned with that of P.93 from B. pertussis. The major differences between the P.70 pertactin from B. parapertussis and the P.69 pertactin from B. pertussis occur in the number of reiterated units within the repeat motifs found in both proteins; the sequence Gly-Gly-Xaa-Xaa-Pro is repeated four times in the P.70 pertactin, and five times in the P.69 pertactin, while the sequence Pro-Gln-Pro occurs nine times in P.70 pertactin and five times in P.69 pertactin. Cloning of the gene for P.95 in an E. coli expression vector results in the synthesis of a protein that mimics native gene expression in B. parapertussis, i.e. the P.95 protein is synthesized and subsequently processed to yield the P.70 form of the protein on the surface of the cell.
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PMID:P.70 pertactin, an outer-membrane protein from Bordetella parapertussis: cloning, nucleotide sequence and surface expression in Escherichia coli. 204 76

Heterotrimeric guanine nucleotide-binding proteins (G proteins) are integral to the signal transduction pathways that mediate the cell's response to many hormones, neuromodulators, and a variety of other ligands. While many signaling processes are guanine nucleotide dependent, the precise coupling between a variety of receptors, G proteins, and effectors remains obscure. We found that the family of genes that encode the alpha subunits of heterotrimeric G proteins is much larger than had previously been supposed. These novel alpha subunits could account for some of the diverse activities attributed to G proteins. We have now obtained cDNA clones encoding two murine alpha subunits, G alpha q and G alpha 11, that are 88% identical. They lack the site that is ordinarily modified by pertussis toxin and their sequences vary from the canonical Gly-Ala-Gly-Glu-Ser (GAGES) amino acid sequence found in most other G protein alpha subunits. Multiple mRNAs as large as 7.5 kilobases hybridize to G alpha q specific probes and are expressed at various levels in many different tissues. G alpha 11 is encoded by a single 4.0-kilobase message which is expressed ubiquitously. Amino acid sequence comparisons suggest that G alpha q and G alpha 11 represent a third class of alpha subunits. A member of this class was found in Drosophila melanogaster. This alpha subunit, DG alpha q, is 76% identical to G alpha q. The presence of the Gq class in both vertebrates and invertebrates points to a role that is central to signal transduction in multicellular organisms. We suggest that these alpha subunits may be involved in pertussis toxin-insensitive pathways coupled to phospholipase C.
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PMID:G protein diversity: a distinct class of alpha subunits is present in vertebrates and invertebrates. 212 49

The putative regulatory effect of opioids on adenylate cyclase was investigated in two different preparations containing, respectively, two different populations of opioid receptors: the rabbit cerebellum (greater than 75% mu-opioid receptors) and the guinea pig cerebellum (greater than 80% kappa-opioid receptors). In the mu-preparation, but not in the kappa-preparation, opioids inhibited the basal and the forskolin-stimulated adenylate cyclase activity in a dose-dependent manner and stereospecifically. The inhibition was in the 20-30% range, required the presence in the assay medium of Mg2+ and of GTP, but was independent of the presence of Na+. Pharmacological characterization of the inhibitory response in the rabbit cerebellum clearly showed that it was under the control of a mu-opioid binding site, with the effect being elicited by non-selective (etorphine and morphine) and mu-selective (Tyr-D-Ala-Gly-Me-Phe-Gly-ol) agonists, whereas delta- and kappa-selective agonists were almost totally ineffective. ADP ribosylation of inhibitory GTP-binding protein by pertussis toxin failed to block the inhibitory effect of opioids, and data presented suggest that this failure is likely to be the consequence of a limited access of the toxin to its substrate in rabbit cerebellum membranes.
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PMID:mu-Opioid receptors and not kappa-opioid receptors are coupled to the adenylate cyclase in the cerebellum. 215 54

Upon exposure to the bacterial chemotactic peptide fMet-Leu-Phe, human neutrophils release lysozyme and generate superoxide anions (O2.-). The synthetic lipoamino acid N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam3Cys), which is derived from the N-terminus of bacterial lipoprotein, when attached to Ser-(Lys)4 [giving Pam3Cys-Ser-(Lys)4], activated O2.- formation and lysozyme release in human neutrophils with an effectiveness amounting to about 15% of that of fMet-Leu-Phe. Palmitic acid, muramyl dipeptide, lipopolysaccharide and the lipopeptides Pam3Cys-Ala-Gly, Pam3Cys-Ser-Gly, Pam3Cys-Ser, Pam3Cys-OMe and Pam3Cys-OH did not activate O2.- formation. Pertussis toxin, which ADP-ribosylates guanine-nucleotide-binding proteins (G-proteins) and functionally uncouples formyl peptide receptors from G-proteins, prevented activation of O2.- formation by fMet-Leu-Phe and inhibited Pam3Cys-Ser-(Lys)4-induced O2.- formation by 85%. Lipopeptide-induced exocytosis was pertussis-toxin-insensitive. O2.- formation induced by Pam3Cys-Ser-(Lys)4 and fMet-Leu-Phe was enhanced by cytochalasin B, by a phorbol ester and by a diacylglycerol kinase inhibitor. Addition of activators of adenylate cyclase and removal of extracellular Ca2+ inhibited O2.- formation by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 to different extents. Pam3Cys-Ser-(Lys)4 synergistically enhanced fMet-Leu-Phe-induced O2.- formation and primed neutrophils to respond to the chemotactic peptide at non-stimulatory concentrations. Our data suggest the following. (1) Pam3Cys-Ser-(Lys)4 activates neutrophils through G-proteins, involving pertussis-toxin-sensitive and -insensitive processes. (2) The signal transduction pathways activated by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 are similar but not identical. (3) In inflammatory processes, bacterial lipoproteins and chemotactic peptides may interact synergistically to activate O2.- formation, leading to enhanced bactericidal activity.
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PMID:Activation of superoxide formation and lysozyme release in human neutrophils by the synthetic lipopeptide Pam3Cys-Ser-(Lys)4. Involvement of guanine-nucleotide-binding proteins and synergism with chemotactic peptides. 216 Feb 37

Pertussis toxin (PT) is an important protective antigen in vaccines against whooping cough, and a genetically detoxified PT analog is the preferred form of the immunogen. Several amino acids of the S1 subunit were identified as functionally critical residues by site-directed mutagenesis, specifically, those at positions 9, 13, 26, 35, 41, 58, and 129. Eighty-three mutated PT operons were introduced into Bordetella parapertussis, and the resultant toxin analogs were screened for expression levels, enzymatic activity, residual toxicity, and antigenicity. While more than half of the mutants were found to be poorly secreted or assembled, the rest were fully assembled and most were highly detoxified. Single mutations resulted in up to a 1,000-fold reduction in both toxic and enzymatic activities, while PT analogs with multiple mutations (Lys-9 Gly-129, Glu-58 Gly-129, and Lys-9 Glu-58 Gly-129) were 10(6)-fold detoxified. Operons coding for stable and nontoxic mutants shown to express a critical immunodominant protective epitope were returned to the chromosome of Bordetella pertussis by allelic exchange. In vivo analysis of the toxin analogs showed a dramatic reduction in histamine sensitization and lymphocytosis-promoting activities, paralleling the reduction in toxic activities. All mutants were protective in an intracerebral challenge test, and the Lys-9 Gly-129 analog was found to be significantly more immunogenic than the toxoid. PT analogs such as those described represent suitable components for the design of a recombinant whooping cough vaccine.
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PMID:Engineering of genetically detoxified pertussis toxin analogs for development of a recombinant whooping cough vaccine. 222 37

During the course of whooping cough, Bordetella pertussis interacts with alveolar macrophages and other leukocytes on the respiratory epithelium. We report here mechanisms by which these bacteria adhere to human macrophages in vitro. Whole bacteria adhere by means of two proteins, filamentous hemagglutinin (FHA) and pertussis toxin, either of which is sufficient to mediate adherence. FHA interacts with two classes of molecules on macrophages, galactose-containing glycoconjugates and the integrin CR3 (alpha M beta 2, CD11b/CD18). The interaction between CR3 and FHA involves recognition of the Arg-Gly-Asp (RGD) sequence at positions 1097-1099 in FHA. This study demonstrates that bacterial adherence can be based on the interaction of a bacterial adhesin RGD sequence with an integrin and that bacterial adhesins can have multiple binding sites characteristic of eukaryotic extracellular matrix proteins.
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PMID:Recognition of a bacterial adhesion by an integrin: macrophage CR3 (alpha M beta 2, CD11b/CD18) binds filamentous hemagglutinin of Bordetella pertussis. 236 31

Filamentous hemagglutinin is a surface-associated adherence protein of Bordetella pertussis, which is a component of some new acellular pertussis vaccines. The nucleotide sequence of an open reading frame that encompasses the filamentous hemagglutinin structural gene, fhaB, suggests that proteolytic processing is necessary to generate the mature 220-kDa filamentous hemagglutinin product. An Arg-Gly-Asp (RGD) tripeptide is found within filamentous hemagglutinin that may be involved in its adherence properties. An internal in-frame deletion in fhaB, encompassing the RGD region, causes loss of B. pertussis-binding to ciliated eukaryotic cells, confirming a potential role for this protein in host-cell binding and infection.
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PMID:Filamentous hemagglutinin of Bordetella pertussis: nucleotide sequence and crucial role in adherence. 253 96

Chronic infusion of morphine to guinea pigs produced selective changes in mu agonist binding properties in cerebrocortical membrane preparations. Employing the mu-selective opioid agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) in direct binding studies and in competition of labeled antagonist binding, we found that the major changes were a decrease in the number of sites with high affinity for agonist, a small reduction in total receptor number, and a loss in the ability of guanosine 5'-[gamma-thio]triphosphate to regulate binding. A fraction of high-affinity mu receptors appeared to retain their high affinity for agonist and their sensitivity to guanine nucleotide analogue after the induction of morphine tolerance, possibly because the morphine concentrations achieved in brain were insufficient to uncouple all mu receptors from associated guanine nucleotide-binding regulatory proteins. Some membrane preparations were treated with pertussis toxin, which has been shown to functionally uncouple mu opioid receptors from their effector systems. In these preparations, a single agonist-affinity state of the receptor was observed. The apparent dissociation constant for this affinity state in pertussis toxin-treated membranes was similar to the lower-affinity state observed in preparations from morphine-tolerant animals. In contrast to the changes observed at mu opioid binding sites, no significant changes in agonist affinity or binding density were observed for selective delta or kappa agonists, consistent with the development of selective tolerance at mu receptors.
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PMID:Selective changes in mu opioid receptor properties induced by chronic morphine exposure. 254 12


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