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)

In this study we investigated the short-term effect of somatostatin on histamine synthesis in a cell population isolated from rabbit gastric mucosa and enriched in enterochromaffin-like cells. Somatostatin inhibited basal and gastrin-stimulated histamine synthesis through a dual mechanism involving a decrease in the affinity of histidine decarboxylase (HDC) for its substrate (L-histidine) and a reduction in the number of functional HDC molecules. H-89 (an inhibitor of cAMP-dependent protein kinase) mimicked somatostatin-induced reduction of HDC affinity, which, on the contrary, was selectively reversed by pertussis toxin (PTX). Furthermore, forskolin was shown to reverse the inhibitory effect of H-89 and to prevent the somatostatin-induced reduction in HDC affinity for L-histidine. Thus, the somatostatin-induced reduction in affinity seems to involve a PTX-sensitive G protein and an inhibition of the cAMP-dependent pathway. On the other hand, the somatostatin-induced decrease in the number of functional HDC molecules seems to be PTX insensitive and independent from a modulation of the cAMP pathway, and does not seem to involve a significant change in HDC messenger RNA expression or a regulation of protein kinase C. The exact nature of this second mechanism will need further studies to be elucidated.
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PMID:Short-term inhibitory effect of somatostatin on gastric histamine synthesis. 904 95

Effects of vasoactive intestinal peptide (VIP) on T cell migration are mediated by structurally distinct types I (VIPR1) and II (VIPR2) G protein-associated receptors. The two receptor types were proposed to transduce opposite effects on human T cells, since cytokine-induced chemotaxis of VIPR1-bearing HuT 78 human T cells, in contrast to T cells that express VIPR2, was inhibited by VIP. We studied chemotactic effects of VIP and related agonists with different affinities for VIP- and peptide histidine-isoleucine (PHI)-related receptors. All, VIP, secretin (SEC), a specific ligand for VIPR1, helodermin (HEL), an activator of helodermin-preferring VIPR2, as well as PHI, stimulated chemotaxis into micropore filters of both normal human peripheral blood T and B cells. Involvement of VIPRs was supported by inhibition of VIP-related agonist-induced migration of T and B cells with a VIPR antagonist. Peripheral blood lymphocyte (PBL) chemotaxis to VIP, SEC, HEL and PHI was reduced by inhibition of tyrosine kinase and pertussis or cholera toxin, whereas inhibition of protein kinase C only affected SEC-induced chemotaxis of PBL significantly. VIP-related agonists induced deactivation of migration at high concentrations. Findings in PBL suggest that VIPR1 activation can stimulate normal T and B cell chemotaxis. Different signaling mechanisms may be involved in mediating chemotactic activation of VIPRs and PHIRs, which may allow further exploration of receptor-dependent mechanisms and signaling pathways of VIP as mediator of PBL functions.
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PMID:Similar involvement of VIP receptor type I and type II in lymphocyte chemotaxis. 967 Aug 47

An efficient one-step affinity purification of bovine brain G protein betagamma subunits (betagamma's) is described. The betagamma's, in a detergent extract of brain membranes, are first dissociated from the alpha subunits (alpha's), reassociated with decahistidine-tagged alphail produced in bacteria, and then adsorbed onto Ni2+-nitrilotriacetic acid-agarose via the histidine tag. This mild adsorption retained the high activity of the ligand alpha's, in contrast to the commonly used chemical crosslinking methods. A wash step with a buffer containing chaotropic ions (SCN-) completely removed contaminating proteins that were refractory to washes with high concentrations of detergents, after which the highly purified betagamma's were eluted with a buffer containing Al3+, Mg2+, and F- ions. The obtained betagamma's were found to be fully functional, as assessed by their ability to support pertussis toxin-catalyzed ADP-ribosylation of alphail. Since the combination of the mild adsorption via the histidine tag and the wash with chaotropic ions can be easily applied to purifying betagamma's from various animal tissues, this new chromatographic method is expected to facilitate the purification of other membrane proteins that bind to Galpha and/or Galphabetagamma.
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PMID:One-step affinity purification of the G protein betagamma subunits from bovine brain using a histidine-tagged G protein alpha subunit. 1004 77

For most, if not all, organisms, iron (Fe) is an essential element. In response to the nutritional requirement for Fe, bacteria evolved complex systems to acquire the element from the environment. The genes encoding these systems are often coordinately regulated in response to the Fe concentration. Recent investigations revealed that Bordetella avium, a respiratory pathogen of birds, expressed a number of Fe-regulated genes (T. D. Connell, A. Dickenson, A. J. Martone, K. T. Militello, M. J. Filiatraut, M. L. Hayman, and J. Pitula, Infect. Immun. 66:3597-3605, 1998). By using manganese selection on an engineered strain of B. avium that carried an Fe-regulated alkaline phosphatase reporter gene, a mutant was obtained that was affected in expression of Fe-regulated genes. To determine if Fe-dependent regulation in B. avium was mediated by a fur-like gene, a fragment of the B. avium chromosome, corresponding to the fur locus of B. pertussis, was cloned by PCR. Sequencing revealed that the fragment from B. avium encoded a polypeptide with 92% identity to the Fur protein of B. pertussis. In vivo experiments showed that the cloned gene complemented H1780, a fur mutant of Escherichia coli. Southern hybridizations and PCRs demonstrated that the manganese mutant had a deletion of 2 to 3 kbp of nucleotide sequence in the region located immediately 5' of the fur open reading frame. A spontaneous PCR-derived mutant of the B. avium fur gene was isolated that encoded a Fur protein in which a histidine was substituted for an arginine at amino acid position 18 (R18H). Genetic analysis showed that the R18H mutant gene when cloned into a low-copy-number vector did not complement the fur mutation in H1780. However, the R18H mutant gene was able to complement the fur mutation when cloned into a high-copy-number vector. The cloned wild-type fur gene will be useful as a genetic tool to identify Fur-regulated genes in the B. avium chromosome.
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PMID:Genetic characterization of wild-type and mutant fur genes of Bordetella avium. 1033 37

delta-Opioid receptors belong to the superfamily of G protein-coupled receptors, characterized by seven putative transmembrane domains, and have been shown to interact with a host of effector systems. It has been suggested that the charge on the conserved aspartic acid residue at position 128 in transmembrane domain 3 of the delta-opioid receptor contributes to both the conformation of the receptor binding pocket and the molecular rearrangements which accompany the establishment of high-affinity states of the receptor. In light of this, we used site-directed mutagenesis to determine whether this residue participates in the transmission of signals to adenylyl cyclase, the effector with which opioid receptors have been classically associated. Substitution of this aspartic acid (D128) for the neutral amino acid alanine, or the protonated amino acids lysine and histidine, constitutively couples the receptor to adenylyl cyclase, as evidenced by a curtailed response to forskolin stimulation in transfected cells. In addition, this constitutive activity can be blocked by pretreatment of the transfected cells with pertussis toxin. Interestingly, naloxone blocks this effect in cells expressing the D128A mutant, but acts as an agonist at the D128K mutant. Our findings support the hypothesis that the interaction between agonist and receptor promotes conformational changes that may be mimicked, at least in part, by mutation of the aspartate residue at position 128. Furthermore, these changes appear to be involved not only in receptor activation, but also in the functional discrimination between agonists and antagonists.
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PMID:Altered adenylyl cyclase responsiveness subsequent to point mutations of Asp 128 in the third transmembrane domain of the delta-opioid receptor. 1047 67

In this study, Gbeta specificity in the regulation of Gbetagamma-sensitive phosphoinositide 3-kinases (PI3Ks) and phospholipase Cbeta (PLCbeta) isozymes was examined. Recombinant mammalian Gbeta(1-3)gamma(2) complexes purified from Sf9 membranes stimulated PI3Kgamma lipid kinase activity with similar potency (10-30 nm) and efficacy, whereas transducin Gbetagamma was less potent. Functionally active Gbeta(5)gamma(2) dimers were purified from Sf9 cell membranes following coexpression of Gbeta(5) and Ggamma(2-His). This preparation as well as Gbeta(1)gamma(2-His) supported pertussis toxin-mediated ADP-ribosylation of Galpha(i1). Gbeta(1)gamma(2-His) stimulated PI3Kgamma lipid and protein kinase activities at nanomolar concentrations, whereas Gbeta(5)gamma(2-His) had no effect. Accordingly, Gbeta(1)gamma(2-His), but not Gbeta(5)gamma(2-His), significantly stimulated the lipid kinase activity of PI3Kbeta in the presence or absence of tyrosine-phosphorylated peptides derived from the p85-binding domain of the platelet derived-growth factor receptor. Conversely, both preparations were able to stimulate PLCbeta(2) and PLCbeta(1). However, Gbeta(1)gamma(2-His), but not Gbeta(5)gamma(2-His), activated PLCbeta(3). Experimental evidence suggests that the mechanism of Gbeta(5)-dependent effector selectivity may differ between PI3K and PLCbeta. In conclusion, these data indicate that Gbeta subunits are able to discriminate among effectors independently of Galpha due to selective protein-protein interaction.
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PMID:Gbeta 5gamma 2 is a highly selective activator of phospholipid-dependent enzymes. 1078 95

Biophysical and biochemical properties of signalling proteins or domains derived from the unorthodox EvgAS and BvgAS two-component phosphorelay systems of Escherichia coli and Bordetella pertussis were investigated. Oligomerization of the effector proteins EvgA and BvgA and of truncated EvgS and BvgS derived signalling proteins containing the receiver and histidine containing phosphotransfer (HPt) domains or comprising only the HPt domains were characterized by native gel electrophoresis, gel permeation experiments and analytical ultracentrifugation. The results obtained by the different methods are consistent with non-phosphorylated EvgA and BvgA proteins being dimers in solution with a dissociation constant significantly below 1 microM. In contrast, all sensor derived domains of EvgS and BvgS were observed to be monomers in vitro. No indications for a phosphorylation induced stimulation of oligomerization of the C-terminal histidine kinase domains could be detected. In agreement with these data, surface plasmon resonance studies revealed a 2:1 stoichiometry in the interaction of EvgA with the immobilized EvgS HPt domain and an affinity constant of 1. 24x10(6) M(-1).
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PMID:Dimerization of signalling modules of the EvgAS and BvgAS phosphorelay systems. 1082 46

We examined a neuronal cell system in which single-cell expression of either familial Alzheimer's disease (FAD) gene V642I-APP or K595N/M596L-APP (NL-APP) in an inducible plasmid was controlled without affecting transfection efficiency. This system revealed that (i) low expression of both mutants exerted toxicity sensitive to both Ac-DEVD-CHO (DEVD) and glutathione ethyl ester (GEE), whereas wild-type APP (wtAPP) only at higher expression levels caused GEE/DEVD-resistant death to lesser degrees; (ii) toxicity by the V642I mutation was entirely GEE/DEVD sensitive; and (iii) toxicity by higher expression of NL-APP was GEE/DEVD resistant. The GEE/DEVD-sensitive death was sensitive to pertussis toxin and was due to G(o)-interacting His(657)-Lys(676) domain. The GEE/DEVD-resistant death was due to C-terminal Met(677)-Asn(695). APP mutants lacking either domain unraveled elaborate intracellular cross-talk between these domains. E618Q-APP, responsible for non-AD type of a human disease, only exerted GEE/DEVD-resistant death at higher expression. Therefore, (i) different FAD mutations in APP cause neuronal cell death through different cytoplasmic domains via different sets of mechanisms; (ii) expression levels of FAD genes are critical in activating specific death mechanisms; and (iii) toxicity by low expression of both mutants most likely reflects the pathogenetic mechanism of FAD.
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PMID:Multiple mechanisms underlie neurotoxicity by different types of Alzheimer's disease mutations of amyloid precursor protein. 1093 5

Constitutive and agonist-dependent activation of the recombinant human 5-HT(1A) receptor (RC: 2.1.5HT.01A) was investigated by co-expression with a rat G(alphai3) protein in Cos-7 cells. The interaction between the 5-HT(1A) receptor and rat G(alphai3) protein was modulated by substitution of the G(alphai3) protein site for pertussis toxin-catalysed ADP-ribosylation (cysteine(351)) by each of the natural amino acids. Enhanced basal [(35)S]GTPgammaS binding responses (+24 to +189%) were observed with the mutant G(alphai3) proteins containing at position 351 either a histidine, glutamine, serine, tyrosine or a nonpolar amino acid with the exception of a proline. With each of these mutant G(alphai3) proteins, spiperone (10 microM), but not WAY 100635 (10 microM), reduced (-22 to -60%, p<0.05) the enhanced basal [(35)S]GTPgammaS binding response. 5-HT (10 microM)-mediated [(35)S]GTPgammaS binding responses attained for some of the mutant G(alphai3)Cys(351) proteins (Phe, Met, Val and Ala) more than 300% of that obtained with the wt G(alphai3) protein. Similar results were also obtained with the prototypical 5-HT(1A) agonist 8-OH-DPAT and the partial agonist (-)-pindolol. Fusion proteins assembled from the 5-HT(1A) receptor and either the wt G(alphai3)Cys(351), mutant G(alphai3)Cys(351)Gly or G(alphai3)Cys(351)Ile protein displayed similar observations for these ligands as obtained by co-expression of the 5-HT(1A) receptor with each of these G(alphai3) proteins. Both the degree of 5-HT(1A) receptor activation by 8-OH-DPAT and (-)-pindolol, and its inhibition by spiperone, strongly correlate (r(2): 0.78-0.81) with the octanol/water partition coefficients of the mutated amino acid at position 351 of the G(alphai3) protein. The present data also suggest the wt G(alphai3) protein does not result in maximal activation of the 5-HT(1A) receptor by the agonists being investigated.
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PMID:Modulation of 5-HT(1A) receptor activation by its interaction with wild-type and mutant g(alphai3) proteins. 1107 69

The unorthodox two-component phosphorelay systems BvgAS and EvgAS of Bordetella pertussis and E. coli, respectively, are suitable model systems to investigate the molecular basis of signalling specificity, because, despite their high relatedness on the sequence level, they do not cross-talk to each other. We could show that the two systems belong to the obligate type of phosphorelay systems and that signalling specificity is mediated by the HPt modules of the histidine kinases and the receiver domains of the effector proteins. To gain more insight into signalling specificity on the molecular level, we started a detailed structural analysis of the respective proteins using a combination of genetic and biochemical methods including limited proteolysis and chemical modification of purified proteins and their mass spectrometrical analysis.
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PMID:Structure-function relationships in the Bvg and Evg two-component phosphorelay systems. 1111 5


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