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)

N-Methyl-D-aspartate (NMDA, 200 microM) evokes the release of [3H]norepinephrine ([3H]NE) from preloaded hippocampal slices. This effect is potentiated by dehydroepiandrosterone sulfate (DHEA S), whereas it is inhibited by pregnenolone sulfate (PREG S) and the high-affinity sigma inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of > or = 100 nM. Neither 3 alpha-hydroxy-5 alpha-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H]NE overflow. The sigma antagonists haloperidol and 1-[2-(3,4-dichlorophenyl)-ethyl]-4-methylpiperazine, although inactive by themselves, completely prevented the effects of DHEA S, PREG S, and 1,3-di(2-tolyl)guanidine on NMDA-evoked [3H]NE release. Progesterone (100 nM) mimicked the antagonistic effect of haloperidol and 1-[2-(3,4-dichlorophenyl)ethyl]-4-methyl-piperazine. These results indicate that the tested steroid sulfate esters differentially affected the NMDA response in vitro and suggest that DHEA S acts as a sigma agonist, that PREG S acts as a sigma inverse agonist, and that progesterone may act as a sigma antagonist. Pertussis toxin, which inactivates the Gi/o types of guanine nucleotide-binding protein (Gi/o protein) function, suppresses both effects of DHEA S and PREG S. Since sigma 1 but not sigma 2 receptors are coupled to Gi/o proteins, the present results suggest that DHEA S and PREG S control the NMDA response via sigma 1 receptors.
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PMID:Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus. 773 82

Platelet-derived growth factor (PDGF) stimulates mitogenesis and exerts other biologic activities in glomerular mesangial cells. The precise mechanism of PDGF-induced mitogenesis in these cells is not clear. The activation of a signal transducing enzyme, phosphatidylinositol 3 kinase (PI 3 kinase) is associated with mitogenesis. Activation of PI 3 kinase results from stimulation of tyrosine kinase and G-protein-coupled classes of receptors. The synthesis of D3 phosphorylated inositides, the products of this enzymatic reaction, in non-nucleated cells such as blood platelets is dependent upon protein kinase C activation and G-proteins. We studied the activation of PI 3 kinase in response to PDGF in human glomerular mesangial cells. Using a PI 3 kinase 85 kD subunit specific antibody, we detected mesangial cell PI 3 kinase protein as 110 and 85 kD heterodimer. PDGF stimulated PI 3 kinase activity in antiphosphotyrosine immunoprecipitates in a dose-dependent manner showing maximum activation at 12 ng/ml. The antiphosphotyrosine associated PI 3 kinase activity showed biphasic kinetics with a fast peak within two minutes followed by a second peak at 10 minutes. Antiphosphotyrosine and PI 3 kinase immunoprecipitation studies indicated the association of the 85 kD PI 3 kinase subunit with PDGFR. Direct immunoprecipitation with PDGFR beta antibody showed the association of PI 3 kinase activity with the PDGF-receptor. The isoquinoline sulfonyl piperazine compound H7 at concentrations that inhibit PDGF-stimulated PKC activity had no effect on PDGF-stimulated PI 3 kinase activity in antiphospotyrosine immunoprecipitates. These data indicate that PI3 kinase activation is insensitive to PKC. Treatment of mesangial cells with pertussis toxin at concentrations that partially inhibited PDGF-induced DNA synthesis in human mesangial cells did not inhibit PDGF-induced PI 3 kinase activation. These data indicate that PDGF activates PI 3 kinase in mesangial cells and that pertussis toxin-sensitive G-proteins are not involved in PI 3 kinase activation. The data further dissociate activation of PI 3 kinase from mitogenesis in human mesangial cells.
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PMID:PDGF-mediated activation of phosphatidylinositol 3 kinase in human mesangial cells. 793 47

Previous data from our laboratory indicated that the slow Ca2+ channel of vascular smooth muscle cells was regulated by cyclic nucleotides. In the present study, the effects of isoproterenol (ISO) on L-type calcium current (ICa(L)) were investigated in freshly-isolated single smooth-muscle cells from the rabbit portal vein using the whole-cell voltage-clamp technique. With high-Cs+ solution in the pipette and physiolocial salt solution (containing 2.0 mM Ca2+) in the bath, ICa(L) was recorded. At a holding potential of -80 mV, low concentrations of ISO (< or = 100 nM) increased ICa, whereas higher concentrations (1-100 microM) transiently increased ICa but then inhibited it persistently. At 10 microM ISO, ICa was initially increased by 44 +/- 9%, and was subsequently decreased by 24 +/- 3%. Pretreatment of cells with 30 microM H-7 [1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine dihydrochloride] caused the first phase to persist and the second inhibitory phase to disappear. Intracellular application of 1 mM GDP[beta S] (guanosine 5'-O-2-thiodiphosphate) abolished both phases of ISO action. In contrast, intracellular application of 100 microM GTP caused the initial stimulatory phase of ISO action to be significantly potentiated; the later inhibitory phase was slightly diminished. In addition, the activated G protein alpha subunit (Gs alpha) mimicked the stimulatory effect of ISO. Pertussis toxin had no effect on either phase of the ISO action. These results suggest that ISO modulates the Ca2+ channel through mechanisms that involve the pertussis-toxin-insensitive G protein(s).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoproterenol modulates the calcium channels through two different mechanisms in smooth-muscle cells from rabbit portal vein. 797 Nov 66

The effects of zinc hydroxide on the respiratory burst and phagocytosis by rat neutrophils were examined. Zinc hydroxide induced an increase in oxygen consumption and O2- production. Electronmicroscopy showed that neutrophils engulfed zinc hydroxide particles by phagocytosis. Pertussis toxin (0.25, 0.5, 1.0 micrograms/ml) and EGTA (1, 2, 5 mM) inhibited zinc hydroxide-induced O2- production in a dose-dependent manner. The inhibitors of protein kinase C, 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide inhibited zinc hydroxide-induced O2- production with IC50 values ranging between 10 microM and 25 microM. The inhibitory study using an inhibitor of myosin light chain kinase, 1-(5-iodo-naphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine, showed IC50 values ranging from 5 microM to 10 microM. These findings indicate that zinc hydroxide induces respiratory burst and phagocytosis by rat neutrophils.
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PMID:Zinc hydroxide induced respiratory burst in rat neutrophils. 815 83

Bradykinin caused graded contraction in the guinea pig ileum, trachea and urinary bladder and rat uterus and vas deferens in vitro. The order of potency (EC50, nM) was: ileum (3) > uterus (5) > trachea (15) > vas deferens (41) > urinary bladder (52) and the maximal responses (percentage to 80 mM KCl) were: 152 +/- 8 (ileum), 122 +/- 6 (uterus), 97 +/- 3 (urinary bladder), 75 +/- 5 (trachea) and 33 +/- 3 (vas deferens). Responses to bradykinin in guinea pig ileum and urinary bladder and rat vas deferens and uterus were markedly attenuated in Ca(2+)-free medium with or without EGTA or by nicardipine, whereas those in guinea pig trachea depended almost exclusively on intracellular Ca2+ sources which were sensitive to ryanodine. Treatment of the animals with pertussis toxin only inhibited bradykinin-induced contraction of the rat uterus. Furthermore, the protein kinase C inhibitors, H7 (5-isoquinolinysulfonyl-2-methyl-piperazine) and staurosporine, antagonized in a graded manner bradykinin responses in guinea pig ileum and trachea and rat vas deferens, indicating the possible dependence on activation of protein kinase C mechanisms, while responses of the rat uterus rely on coupling by a pertussis toxin-sensitive G protein. Thus, bradykinin acting at B2 receptors may induce contractions in several smooth muscles from rat and guinea pig through activation of multiple second messenger pathways.
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PMID:Multiple mechanisms of bradykinin-induced contraction in rat and guinea pig smooth muscles in vitro. 852 11

5-Hydroxytryptamine 5-HT1B/5-HT1D receptors are members of the same receptor subfamily, but display a different pharmacology (Hartig et al. (1992) Trends Pharmacol Sci 13: 152-159). Whereas several cell lines have been reported to contain 5-HT1B receptors, none has been described, however, that endogenously expresses well-characterized 5-HT1D receptors. The present study deals with the identification of 5-HT1D receptors inhibiting cyclic AMP accumulation in Madin-Darby canine kidney (MDCK) cells. 5-HT (1 nM-10 microM) induced a concentration-dependent inhibition of the cyclic AMP accumulation stimulated by prostaglandin E1 (1 microM) in MDCK cells. The maximal effect of 5-HT averaged 50% inhibition and was abolished after a pre-treatment of the cells with pertussis toxin. Other agonists mimicked the effects of 5-HT, with the following rank order of potency (pEC50 +/- SEM, n > or = 3): 5-carboxamidotryptamine (8.36 +/- 0.48) > PAPP (p-aminophenylethyl-m-trifluoromethylphenyl piperazine. 7.89 +/- 0.23) > 5-HT (7.35 +/- 0.05) > sumatriptan (6.65 +/- 0.27). PAPP behaved as a partial agonist. 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) was less potent, its maximal effect being not reached at 0.1 mM. Methiothepin. GR127935, (-)propranolol, rauwolscine and ketanserin were all devoid of intrinsic activity (up to 10 microM or 0.1 mM). Methiothepin (10 nM. 0.1 microM and 1 microM) antagonized 5-HT effect (pA2 8.57 +/- 0.44. Schild slope 1.17 +/- 0.21, n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine 5-HT1D receptors mediating inhibition of cyclic AMP accumulation in Madin-Darby canine kidney (MDCK) cells. 858 40

The regulation in expression of human 5-hydroxytryptamine1A (5-HT1A) receptors by agonists and antagonists was studied in a stable transfected Chinese hamster ovary cell line expressing the human 5-HT1A receptor. Receptor density and affinity were measured with [125I]4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-iodobenzamido ]ethyl]piperazine ([125I]p-MPPI), a selective antagonist of 5-HT1A receptors. Treatment of Chinese hamster ovary cells with serotonin or the selective agonist (+/-)-8-hydroxy-N,N-dipropyl-2-aminotetralin stimulated a 2.5-fold increase in receptor density. The antagonists 4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-iodobenzamidoethyl] piperazine, (-)-(S)-pindolol, and spiperone also stimulated up-regulation of receptor expression. Agonist- and antagonist-stimulated up-regulations of receptor expression were mechanistically different. The effect of agonists was inhibited by pertussis toxin, actinomycin D, and cycloheximide. Antagonist-stimulated up-regulation was inhibited by cycloheximide, only partially inhibited by actinomycin D, and not inhibited by pertussis toxin. In the course of identifying potential pathways for coupling of the receptor to activation of transcription, we demonstrated that agonists activate the transcription regulatory factor nuclear factor-kappaB (NF-kappaB). Agonists were found to stimulate degradation of the inhibitory subunit, IkappaB alpha, and to increase the activity of a NF-kappaB-dependent CAT reporter gene. In contrast, the antagonist 4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-p-iodobenzamidoethyl] piperazine neither elicited degradation of Ikappa-B alpha nor increased reporter activity. Our data suggest that expression of 5-HT1A receptors can be regulated by both agonists and antagonists and that the agonist but not antagonist stimulation occurs concomitantly with activation of NF-kappaB.
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PMID:5-hydroxytryptamine1A receptor-mediated increases in receptor expression and activation of nuclear factor-kappaB in transfected Chinese hamster ovary cells. 927 44

1. The effect of the non-steroidal anti-inflammatory drugs naproxen, mefenamic acid, phenylbutazone, piroxicam and tolmetin on the vanadate (0.3 mM)-induced tonic contraction, as well as the modifications of these effects by the G-protein inhibitor pertussis toxin, and the inhibitors of protein kinase A, Rp-cAMPS (Rp-Adenosine 3',5'-cyclic monophosphothioate triethylamine salt) and protein kinase C, H-7 [1(5-isoquinolynilsulfonyl)-2-methyl-piperazine], have been assayed to study the possible nature of intracellular mediators contributing to the inhibitory effects of NSAIDs in rat uterine smooth muscle incubated in medium lacking calcium plus EDTA. The effect of phorbol 12,13-dibutyrate on vanadate contraction and its modification with H-7 has also been examined. 2. Naproxen (6-600 microM), mefenamic acid (6-300 microM), phenylbutazone (6-300 microM), piroxicam (6-600 microM) and tolmetin (6-600 microM) produced concentration-dependent relaxation of vanadate-induced tonic contraction. The potency order, in accordance with their respective IC50 values was: phenylbutazone > or = mefenamic acid > or = naproxen > tolmetin > or = piroxicam. 3. The relaxant effects of naproxen, phenylbutazone, piroxicam and tolmetin were significantly antagonized with pertussis toxin (50 ng ml-1), Rp-cAMPS (100 microM) and H-7 (1 microM). However, the effect of mefenamic acid was unmodified by the three drugs. This suggests that the effect of mefenamic acid and other NSAIDs occur by different mechanisms. 4. Phorbol 12,13-dibutyrate relaxed the vanadate contraction but the maximal relaxation achieved (54.8 +/- 8.3%, n = 4) was lower than those induced with the NSAIDs. On the other hand, H-7 (1 microM) did not modify the relaxant effect of phorbol 12,13-dibutyrate. This suggests that H-7 behaves as a PKA, but not a PKC inhibitor, under the present experimental conditions. 5. The relaxation by naproxen, phenylbutazone, piroxicam and tolmetin is presumably produced by increasing cAMP because the effects of these are antagonized with Rp-cAMPS and H-7, and by pertussis-toxin-sensitive mechanisms.
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PMID:Contribution of cAMP to the inhibitory effect of non-steroidal anti-inflammatory drugs in rat uterine smooth muscle. 972 23

The actions of serotonin on rat basolateral amygdala neurons were studied with conventional intracellular recording techniques and fura-2 fluorimetric recordings. Bath application of 5-hydroxytryptamine (5-HT or serotonin) reversibly suppressed the excitatory postsynaptic potential in a concentration-dependent manner without affecting the resting membrane potential and neuronal input resistance. Extracellular Ba2+ or pertussis toxin pretreatment did not affect the depressing effect of 5-HT suggesting that it is not mediated through activation of Gi/o protein-coupled K+ conductance. The sensitivity of postsynaptic neurons to glutamate receptor agonist was unaltered by the 5-HT pretreatment. In addition, the magnitude of paired-pulse facilitation was increased in the presence of 5-HT indicating a presynaptic mode of action. The effect of 5-HT was mimicked by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and was blocked by the selective 5-HT1A antagonist 1-(2-methoxyphenyl)-4[4-(2-phthalimido)butyl]piperazine oxadiazol-3-yl]methyl]phenyl]-methanesulphonamide. In contrast, the selective 5-HT2 receptor antagonist ketanserin failed to affect the action of 5-HT. The effects of 5-HT and 8-OH-DPAT on the high K+-induced increase in [Ca2+]i were studied in acutely dissociated basolateral amygdala neurons. High K+-induced increase in [Ca2+]i was blocked by Ca2+-free solution and Cd2+ suggesting that Ca2+ entry responsible for the depolarization-evoked increase in [Ca2+]i occurred through voltage-dependent Ca2+ channels. Application of 5-HT and 8-OH-DPAT reduced the K+-induced Ca2+ influx in a concentration-dependent manner. The effect of 5-HT was completely abolished in slices pretreated with Rp-cyclic adenosine 3',5'-monophosphothioate (Rp-cAMP), a regulatory site antagonist of protein kinase A, suggesting that 5-HT may act through a cAMP-dependent mechanism. Taken together, these results suggest that functional 5-HT1A receptors are present in the excitatory terminals and mediate the 5-HT inhibition of synaptic transmission in the amygdala.
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PMID:Serotonin depresses excitatory synaptic transmission and depolarization-evoked Ca2+ influx in rat basolateral amygdala via 5-HT1A receptors. 975 2

G protein-coupled receptors exist in G protein-coupled and -uncoupled forms that exhibit high and low affinity for agonists, respectively. Consequently, affinity differences of a compound for the high vs. the low affinity state of a receptor have been used to estimate its intrinsic activity at that receptor. We examined the affinity of a series of compounds for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor sites labeled with 0.2 nM [3H](+/-)-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) (high affinity), or with 0.25 nM [3H]4-(2'-methoxy-)-phenyl-1-[2'-(N-2"-pyridyl)-p-fluorobenzamido] eth yl-piperazine ([3H]p-MPPF) in the presence of 100 microM guanylylimidodiphosphate (Gpp(NH)p) (low affinity) in rat hippocampal membranes. For a variety of 5-HT(1A) receptor ligands, the low/high affinity ratio (ranging from 110 for 5-HT to 0.12 for spiperone) was in good agreement with their reported intrinsic activity. Positive rank correlations were found between low/high affinity ratios and intrinsic activities (E(max) values) reported in the literature. The high efficacy 5-HT(1A) receptor agonists, 1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)piperaz ine (S-14506) and dihydroergotamine, however, had similar, high affinity for both G protein-coupled and -uncoupled forms of the receptor. The Hill coefficients for both compounds were markedly higher than 1.0, suggesting that positive cooperativity could be responsible for the unexpected results. The 5-HT(1A) receptor agonist activity of dihydroergotamine and S-14506, assessed by measuring the inhibition of forskolin-stimulated cAMP accumulation, was blocked completely by pertussis toxin, reinforcing the suggested involvement of an inhibitory G protein in their effects. Taken together, the results suggest that, although the low/high affinity ratio of a ligand for 5-HT(1A) receptors generally covaries with its intrinsic activity, dihydroergotamine and S-14506 may interact with 5-HT(1A) receptors in a manner different from that of other 5-HT(1A) receptor agonists. Their effects, however, appear to be G(i) protein-dependent.
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PMID:Correlation between low/high affinity ratios for 5-HT(1A) receptors and intrinsic activity. 1061 69


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