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)

The molecular basis for the regulation of high-affinity agonist, [3H]N-n-propylnorapomorphine ([3H]NPA), binding to cholate-solubilized dopamine D2 receptors was characterized using cations, guanine nucleotides and sulfhydryl-modifying agents. [3H]NPA binding displayed an absolute requirement for divalent cations in the solubilized preparation. Removal of Na+ from the solubilized preparation caused an apparent reconstitution of soluble receptors resulting in a reduced sensitivity of the agonist binding to divalent cations. The pharmacological profile of [3H]NPA binding was found to be similar in membrane and solubilized preparations. N-ethylmaleimide (NEM) and thermal exposure mimicked the effects of guanine nucleotides in reducing the proportion of high-affinity agonist sites in the solubilized state. [3H]NPA binding was much more susceptible to NEM-induced alkylation or heat inactivation compared to the antagonist [3H]spiroperidol binding. Pertussis-toxin-catalyzed ADP-ribosylation of G-proteins in the solubilized preparation resulted in the labelling of only one protein with the apparent molecular weight of 39-41 kDa. Both NEM and heat treatments caused the loss of ADP-ribosylation in the solubilized preparations. A consistent pattern of correlation between receptor binding data and ADP-ribosylation response suggests functional coupling of dopamine D2 receptors to the components of the effector system in solution.
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PMID:Functional modifications of the coupling of solubilized dopamine D2 receptors to guanine-nucleotide-binding proteins. 136 39

To examine whether GTP-binding proteins (G proteins) mediate the ability of neurotensin to lower the affinity of dopamine D2 agonist binding, the modulation by neurotensin in vitro of N-[3H]propylnorapomorphine [( 3H]-NPA) binding was investigated following pretreatment with pertussis toxin and N-ethylmaleimide in rat neostriatal membranes. Preincubation with N-ethylmaleimide (100 microM) markedly inhibited pertussis toxin-induced back-ADP ribosylation of three proteins with apparent molecular masses of 41, 40, and 39 kDa, respectively. This inhibition was prevented by adding dithiothreitol (250 microM) during the preincubation. N-Ethylmaleimide increased the KD (180 +/- 30%) and decreased the Bmax (-31 +/- 9%) of [3H]NPA binding sites but did not affect the binding properties of the selective D2 antagonist [3H]raclopride. N-Ethylmaleimide pretreatment did not affect the neurotensin (3 nM)-induced increase in the KD of [3H]NPA binding sites. Pertussin toxin treatment in vivo and in vitro was similarly ineffective. In conclusion, the present study indicates that neurotensin modulation of D2 agonist binding in neostriatal membranes is not mediated by G proteins.
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PMID:Neurotensin decreases the affinity of dopamine D2 agonist binding by a G protein-independent mechanism. 182 79

The D-2 dopamine receptor mediates inhibition of adenylate cyclase in rat intermediate lobe; this receptor is linked to cyclase by the inhibitory guanyl nucleotide-binding protein (Ni). The functioning of components in the inhibitory system was compared in control and pertussis toxin-treated tissues. (-)-N-n-Propylnorapomorphine ((-)-NPA), a dopamine agonist, and 5'-guanylyl imidodiphosphate (Gpp(NH)p), a nonhydrolyzable GTP analog, caused a dose-dependent inhibition of adenylate cyclase in control tissue. Pertussis toxin abolished dopamine receptor-mediated inhibition of adenylate cyclase but did not alter Gpp(NH)p-induced inhibition of cyclase. In control tissue, GTP blocked Gpp(NH)p inhibition of cyclase in the absence, but not in the presence of (-)-NPA. Following pertussis toxin treatment, GTP blocked the inhibitory effect of Gpp(NH)p either in the absence or in the presence of (-)-NPA. Pertussis toxin did not alter the number of dopamine receptors or the affinity of the receptor for [3H]spiroperidol, a dopamine antagonist. However, pertussis toxin decreased the potency of (-)-NPA in the binding assay and abolished the ability of GTP to affect agonist binding. Furthermore, pertussis toxin abolished the dopamine receptor-mediated inhibition of immunoreactive alpha-melanocyte-stimulating hormone release, and induced the ADP-ribosylation of the Mr = 41,000 subunit of Ni.
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PMID:Altered activity of the inhibitory guanyl nucleotide-binding component (Ni) induced by pertussis toxin. Uncoupling of Ni from receptor with continued coupling of Ni to the catalytic unit. 608 7

Dopamine release is activated by ethanol and addicting drugs, but molecular mechanisms linking dopaminergic signaling to neuronal responses and drinking behavior are poorly understood. We report that dopamine-D2 receptors induce PKA Calpha translocation and increase CRE-regulated gene expression. Ethanol also activates PKA signaling. Subthreshold concentrations of the D2 agonist NPA and ethanol, without effect alone, together cause synergistic PKA translocation and CRE-mediated gene transcription. D2 or adenosine A2 receptor blockade, pertussis toxin, Rp-cAMPS, or overexpression of dominant-negative peptides that sequester betagamma dimers prevent synergy. Importantly, overexpression of a betagamma inhibitor peptide in the nucleus accumbens strikingly reduces sustained alcohol consumption. We propose that synergy of D2 and A2 confers ethanol hypersensitivity and that betagamma dimers are required for voluntary drinking.
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PMID:betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. 1208 72

Anaplastic thyroid carcinomas (ATCs) are highly aggressive, extremely lethal human cancers with poor therapeutic response. Chemokines are a superfamily of small cytokine-like proteins that induce, through their interaction with G protein-coupled receptors, cytoskeletal rearrangement, firm adhesion to endothelial cells, and directional migration. In this study, we characterized the expression of CXC chemokine receptor 4 (CXCR4) and analyzed its functions in ARO cells, a human ATC cell. The normal primary cultured thyroid cells and ATC cell lines expressed CXCR4 and stromal cell-derived factor (SDF)-1 alpha transcripts, detected by RT-PCR. Fluorescence activated cell sorting analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA, and normal thyroid cells did not express membrane CXCR4, as determined by fluorescence activated cell sorting analysis. To identify the functional role of CXCR4 in ARO cells, we treated ARO cells with SDF-1 alpha and analyzed the signaling pathways, cellular migration, and proliferation. SDF-1alpha enhanced the migration but did not affect the proliferation of ARO cells or activate the Janus kinase/signal transducer and activator of transcription signaling pathways. However, SDF-1 alpha/CXCR4 activation resulted in phosphorylation of the p70S6 kinase and its target protein, ribosomal S6 protein, and also activation of the ERK1/ERK2 signaling pathways. Furthermore, SDF-1 alpha/CXCR4- mediated activation of the p70S6 kinase and phosphorylation of the S6 protein were inhibited by treatment with an mTOR/FRAP inhibitor. The specificity of the CXCR4-mediated migration of ARO cells was demonstrated by the dose-dependent inhibition of migration by neutralizing anti-CXCR4. The ATC cells, FRO and NPA, which do not express CXCR4, did not demonstrate significant SDF-1 alpha-mediated migration in vitro. In addition, the CXCR4-mediated migration of ARO cells was inhibited by treatment with pertussis toxin (a Gi-protein inhibitor) and PD 98059 (a mitogen-activated ERK kinase inhibitor) but not by LY294002 and wortmanin, phosphatidylinositol 3-kinase inhibitors. These findings suggest that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.
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PMID:CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. 1251 84