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)

Irreversible inactivation of striatal D2 dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or inactivation of striatal guanine nucleotide binding proteins (G proteins) with pertussis toxin (PT) shifted the dose-response curve for N-n-propylnorapomorphine (NPA)-mediated inhibition of gamma-butyrolactone (GBL)-induced elevation of L-3,4-dihydroxyphenylalanine (L-DOPA) to the right, with a decrease in the maximum response. For the partial agonist (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)-3-PPP], in contrast, there was little shift in the ED50, after inactivation of either D2 receptors or G proteins. Completely analogous effects were found at the somatodendritic 5-HT1A autoreceptor in the raphe nuclei, mediating inhibition of the synthesis of serotonin (5-HT); the full agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial agonist, buspirone were utilized to inhibit the synthesis of 5-HT, as measured by changes in levels of L-5-hydroxytryptophan (5-HTP). Additionally, in both systems, combined treatment with pertussis toxin, followed by EEDQ, reduced the maximum effect, when compared to either agent alone but had little further effect on the ED50. In systems exhibiting a large receptor reserve for agonists, such as those described above, the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve.
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PMID:The effects of pertussis toxin on dopamine D2 and serotonin 5-HT1A autoreceptor-mediated inhibition of neurotransmitter synthesis: relationship to receptor reserve. 135 48

Akin to receptor inactivation with phenoxybenzamine (PBZ) (1 microM, 1 hr), treatment of anterior pituitary cells with 17 beta-estradiol (10 nM, 3 days) right-shifted the dose-response curve for inhibition of prolactin (PRL) secretion by the full agonist R-(-)-N-n-propylnorapomorphine (NPA) and reduced the maximal effect [EC50 (pM) and percent maximal effect: control, 25.4 and 81.2; PBZ, 115.3 and 57.9; 17 beta-estradiol, 358 and 58.6]. PBZ treatment of 17 beta-estradiol-pretreated cultures further reduced the maximal response but did not alter the EC50. Plots of receptor occupancy vs. response indicated a large receptor reserve for NPA (approximately 60%) in control cultures but its abolition by 17 beta-estradiol. 17 beta-Estradiol pretreatment elicited identical rightward shifts (4.5-fold) and similar reductions in maximal PRL inhibition by quinpirole and (+)-3-PPP, although these drugs were partial agonists with dissimilar efficacies relative to NPA (0.61 and 0.12, respectively) at presynaptic striatal D2 receptors. However, receptor inactivation experiments with (+)-3-PPP and quinpirole, and subsequent comparison of receptor occupancy vs. response plots, demonstrated that the relative efficacies of quinpirole and (+)-3-PPP were reversed in the striatum and anterior pituitary. In striatum, half-maximal response to quinpirole and (+)-3-PPP required 6.2 and 30% receptor occupancy, respectively, whereas 25.6 and 9.6% occupancy was required in the pituitary. Pertussis toxin treatment (10 ng/ml, 24 hr) produced large shifts in the dose-response curves for all three agonists (8.4-21.9-fold), but was distinguished from the effects of both PBZ and 17 beta-estradiol by a significant (P < .001) decrease in the slope factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative effects of receptor inactivation, 17 beta-estradiol and pertussis toxin on dopaminergic inhibition of prolactin secretion in vitro. 135 7

The effects of the high affinity sigma (sigma) ligands 1,3-di(2-tolyl)guanidine (DTG), (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-yl-amine hydrochloride (JO-1784), (+)3-[3-hydroxyphenyl]-N-(1-propyl)piperidine hydrochloride [(+)3-PPP] and haloperidol were studied on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline (NA) from preloaded hippocampal slices made from Sprague-Dawley rats. The [3H]NA release was evoked once by a 4 min exposure to NMDA, 40 min after the beginning of superfusion with a Mg+(+)-free Krebs' solution. In the absence of any drug, NMDA evoked a concentration-dependent [3H]NA release. Mg++ and EGTA abolished the [3H]NA release induced by NMDA. JO-1784 and (+)3-PPP potentiated in a concentration-dependent manner NMDA-induced [3H]NA release, without affecting the basal outflow. DTG concentration-dependently inhibited the overflow of [3H]NA evoked by NMDA, without affecting the basal efflux. Haloperidol, which did not modify NMDA-evoked [3H]NA release by itself, completely prevented the effects of JO-1784, (+)3-PPP and DTG. In contrast, spiperone, also a potent dopamine receptor antagonist but with low affinity for sigma binding sites, failed to prevent the potentiation of NMDA-evoked release of [3H]NA by JO-1784 and (+)3-PPP. The possible involvement of Gi/o proteins in the modulation by sigma ligands of NMDA-evoked [3H]NA release in the rat hippocampus was also investigated. To this end, Gi/o proteins were inactivated with pertussis toxin (PTX), injected locally 3 to 11 days prior to the experiment or with in vitro preincubation with N-ethylmaleimide (NEM) for 30 min prior the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation by sigma ligands of N-methyl-D-aspartate-induced [3H]noradrenaline release in the rat hippocampus: G-protein dependency. 140 2

The sigma receptor, which is labeled with (+)-[3H]3-(3-hydroxyphenyl)-N- 1-(propyl)piperidine [(+)-[3H]3-PPP], is a site that binds several psychotomimetic opiate benzomorphans and certain antipsychotics, such as haloperidol. In order to elucidate the mechanisms involved in sigma receptor ligand binding, equilibrium binding analysis and kinetics of association and dissociation of the relatively selective sigma receptor ligand (+)-[3H]3-PPP were determined in rat brain membranes in the absence and presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. In the absence of Gpp(NH)p, (+)-3-PPP, cyclazocine, pentazocine, and (+)-SKF 10047 bind to high and low affinity sites (KH = 1.3-7.5 nM; KL = 84-500 nM), as determined by computer assisted analysis of the inhibition of (+)-[3H]3-PPP binding by the sigma ligands. The antipsychotics haloperidol and chlorpromazine inhibit (+)-[3H]3-PPP binding in a manner indicating interaction with a single state of the receptor. Gpp(NH)p (0.1 mM) abolished the high affinity binding component of the sigma agonist-like compounds tested but had no effect on the affinities of the antipsychotics for the receptor. Gpp(NH)p decreased the association rate of (+)-[3H]3-PPP binding 5-fold and also converted the biexponential dissociation kinetics of the ligand, observed in the absence of Gpp(NH)p, to a rapid monophasic dissociation process. Pretreatment of membranes with N-ethylmaleimide and pertussis toxin inhibited (+)-[3H]3-PPP binding and abolished the effect of Gpp(NH)p on the sigma ligand binding. These findings indicate of the sigma receptor is capable of existing in two discrete states, having high and low affinity for sigma agonist-like drugs. The regulation of the high affinity binding state by GTP-binding protein-modifying agents suggests its coupling to GTP-binding protein(s).
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PMID:Multiple affinity binding states of the sigma receptor: effect of GTP-binding protein-modifying agents. 255 9

In this study, the ligand-receptor-G protein interactions of the dopamine D3 receptor expressed in Chinese hamster ovary cells were investigated using guanosine 5'-[gamma-thio]triphosphate-[35S] ([35S]GTPgammaS) and receptor binding experiments. Dopamine stimulated the [35S]GTPgammaS binding in a guanine nucleotide, magnesium and sodium-dependent manner. Dopamine and quinpirole produced maximal stimulation of the [35S]GTPgammaS binding whereas (+)-7-OH-DPAT and (-)-3-PPP were partial agonists. Interestingly, several compounds previously classified as D2 receptor antagonists behaved as inverse agonists at the D3 receptor, i.e., they inhibited the basal [35S]GTPgammaS binding in a dose dependent fashion. Haloperidol, (+)-UH-232, (+)-AJ-76 and raclopride were full inverse agonists but clozapine was a partial inverse agonist. Pertussis toxin treatment abolished the D3 receptor-mediated agonist as well as inverse agonist responses, indicating the involvement of Gi/Go proteins in both processes. According to the ternary complex model, agonists should bind with higher affinity to the G protein coupled receptor (RG) and thereby shift the equilibrium from free receptor (R) toward RG, which produces a biological response. However, an inverse agonist should bind with higher affinity to R than to RG and thereby inhibit the basal activity of the cell. We found that the high affinity agonist binding site (RG) was abolished by pertussis toxin treatment of the cells. However, the inverse agonists bound with the same affinity to untreated and pertussis toxin treated D3 receptor membranes. Thus, we found no evidence for the hypothesis that inverse agonists would shift the equilibrium from RG toward R by binding with higher affinity to R than to RG.
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PMID:Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding. 953 1

In CHO cells transfected with the rat dopamine D2 receptor (long isoform), administration of dopamine per se elicited a concentration-dependent increase in arachidonic acid (AA) release. The maximal effect was 197% of controls (EC50=25 nM). The partial D2 receptor agonist, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP], also induced AA release, but with somewhat lower efficacy (maximal effect: 165%; EC50=91 nM). The AA-releasing effect of dopamine was counteracted by pertussis toxin, by the inhibitor of intracellular Ca2+ release, 8-(N N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), by excluding calcium from the medium, by the phospholipase A2 (PLA2) inhibitor, quinacrine, and by long-term pretreatment with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). In addition, it was antagonized by the D2 antagonists, raclopride and (-)-sulpiride--but not by (+)-sulpiride--and absent in sham-transfected CHO cells devoid of D2 receptors. The results obtained contrast to the previous notion that dopamine and other D2 receptor agonists require the concomitant administration of calcium-mobilizing agents such as ATP, ionophore A-23187 (calcimycin), thrombin, and TRH, to influence AA release from various cell lines.
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PMID:Direct dopamine D2-receptor-mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+-mobilizing agent. 975 80

This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in cloned cells using the cytosensor microphysiometer. Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller than those in adherent CHO cells. The time courses and maximum increases in acidification rate of the agonist responses in adherent CHO cells were different between the three dopamine receptor clones. Responses were blocked by pretreatment of cells with pertussis toxin or amiloride analogues. Most agonists had full intrinsic activity at each of the dopamine receptor subtypes, as compared to quinpirole, however both enantiomers of UH-232 and (-)3-PPP were partial agonists in this assay system. The functional potency of full agonists at each of the three receptors expressed in CHO cells was either higher than, or similar to, the apparent inhibition constants (Ki) determined in [125I]-iodosulpride competition binding studies. Functional selectivities of the agonists were less than radioligand binding selectivities. The rank orders of agonist potencies and selectivities were similar, but not identical, to the rank orders of radioligand binding affinities and selectivities. The dopamine receptor antagonists, iodosulpride and clozapine, had no effect on basal acidification rates but inhibited acidification responses in CHO cells to quinpirole in an apparently competitive manner. Antagonist potencies closely matched their radioligand binding affinities in these cells.
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PMID:Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells. 1045 59