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)

Steroid hormones regulate a host of physiological processes and behaviors. These actions can occur by genomic mechanisms involving gene transcription or by nongenomic mechanisms proposed to involve receptors associated with the plasma membrane. BSA-conjugated steroid hormones have been extensively used to elucidate signal transduction pathways for these hormones. We have previously shown, using calcium imaging, that 17beta-estradiol (E2) significantly increases GnRH-1 neuronal activity. During the course of these experiments, it became apparent that three different BSA-estrogen compounds have been used in a variety of cell types: 17beta-estradiol 6-O-carboxymethyloxime-BSA (E2-6-BSA); 1,3,5(10)-estratrien-3,16alpha,17beta-triol-6-one 6-O-carboxymethyloxime-BSA (E-6-BSA); and 1,3,5(10)-estratrien-3,17beta-diol 17-hemisuccinate-BSA (E2-17-BSA). The effects of these compounds on GnRH-1 neuronal activity were compared using calcium imaging. E-6-BSA and E2-17-BSA, but not E2-6-BSA, significantly increased all parameters of GnRH-1 neuronal activity. In addition, the effects of these two BSA compounds were reversed by the estrogen receptor antagonist ICI 182,780 but not by inhibition of gene transcription. The effects of E2-17-BSA, but not E-6-BSA were reversed by treatment with pertussis toxin, which blocks G protein-coupled receptors. These data indicate that these compounds cannot be used interchangeably and clearly have different binding properties and/or different effects on target tissues.
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PMID:Bovine serum albumin-estrogen compounds differentially alter gonadotropin-releasing hormone-1 neuronal activity. 1553 55

In rat ventricular cardiomyocytes beta2-adrenoceptors (AR) couple to Gs- and Gi-protein, and evidence has accumulated that beta2-AR agonists can differentially activate either Gs- or Gs- and Gi-protein. In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) on beta2-AR agonist (terbutaline (TER), salbutamol (SAL) and fenoterol (FEN)) evoked inhibition of phenylephrine (PE)-induced increase in the rate of protein synthesis (assessed as [3H]phenylalanine incorporation) to find out which beta2-AR agonist activates selectively Gs- or Gs- and Gi-protein. PE (1 microM) increased the rate of protein synthesis from 100% to 130+/-2% (n = 34). FEN, TER and SAL (1 nM-10 microM) inhibited PE-induced increase in the rate of protein synthesis concentration-dependently. FEN inhibited PE effects almost completely (from 132+/-3 to 101+/-1%), whereas TER and SAL caused only partial inhibition (from 131+/-2 to 114+/-2 and 129+/-1 to 111+/-2%, respectively). Pretreatment of cardiomyocytes with PTX (250 ng ml(-1) for 16 h at 37 degrees C) did not affect FEN effects, but converted TER- and SAL-evoked partial inhibition into complete inhibition. Inhibitory effects of the three beta2-AR agonists were markedly attenuated by beta1-AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast, beta2-AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the three beta2-AR agonists only in PTX-pretreated cardiomyocytes,with beta1-AR blocked by CGP. We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the Gs protein-pathway, while TER and SAL activate the Gs- and Gi-protein pathways. Part of the effects of these three beta2-AR agonists appears to be mediated by beta1-AR.
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PMID:Agonist-specific activation of the beta2-adrenoceptor/Gs-protein and beta2-adrenoceptor/Gi-protein pathway in adult rat ventricular cardiomyocytes. 1647 18

Endogenous catecholamines released during myocardial ischemia have been considered both to aggravate cell injury and exacerbate arrhythmias and to exert a protective action on the post-ischemic contractile function. The present work was addressed to look for evidence to explain this controversy. The effects of cardiac catecholamine depletion and of alpha- and beta-adrenoceptor (AR) blockade on the post-ischemic contractile dysfunction, as well as its possible relationship with cardiac oxidative stress, were studied in isolated and perfused rat hearts submitted to 20 min of ischemia and 30 min of reperfusion (stunning). Catecholamine depletion improves the contractile recovery in the stunned heart. This mechanical effect was associated with decreased levels of lipid peroxidation. A similar enhancement of the contractile function during reperfusion was detected after the simultaneous blockade of alpha 1- and beta-ARs with prazosin plus propranolol. To ascertain which specific AR pathway was involved in the effects of catecholamines on the stunned heart, selective AR blockers, prazosin (alpha 1-blocker), atenolol (beta 1-blocker), ICI 118,551 (beta 2-blocker) and selective inhibitors of Gi-PI3K pathway (pertussis toxin and wortmannin) were alternatively combined. The results indicate that catecholamines released during ischemia exert a dual action on the contractile behavior of the stunned heart: a deleterious effect, related to the activation of the beta 2-AR-Gi-PI3K-pathway, which was counteracted by a beneficial effect, triggered by the stimulation of alpha 1-AR. Neither the depression nor the enhancement of the post-ischemic contractile recovery were related with the increase in ROS formation induced by endogenous catecholamines.
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PMID:beta 2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart. 1657 88

A 5-day exposure to morphine exerts a profound cardioprotective phenotype in murine hearts. In the present study, we examined mechanisms by which morphine generates this effect, exploring the roles of G(i) and G(s) proteins, PKA, PKC, and beta-adrenergic receptors (beta-AR) in acute and chronic opioid preconditioning. Langendorff-perfused hearts from placebo, acute morphine (AM; 10 micromol/l)-, or chronic morphine (CM)-treated mice (75-mg pellet, 5 days) underwent 25-min ischemia and 45-min reperfusion. After reperfusion, placebo-treated hearts exhibited marked contractile and diastolic dysfunction [rate-pressure product (RPP), 40 +/- 4% baseline; end-diastolic pressure (EDP), 33 +/- 3 mmHg], whereas AM hearts showed significant improvement in recovery of RPP and EDP (60 +/- 3% and 23 +/- 4 mmHg, respectively; P < 0.05 vs. placebo). Furthermore, CM hearts demonstrated a complete return of diastolic function and significantly greater recovery of contractile function (83 +/- 3%, P < 0.05 vs. both placebo and AM). Pretreatment with G(i) protein inhibitor pertussis toxin abolished AM protection while partially attenuating CM recovery (P < 0.05 vs. placebo). Treatment with G(s) inhibitor NF-449 did not affect AM preconditioning yet completely abrogated CM preconditioning. Similarly, PKA inhibition significantly attenuated the ischemia-tolerant state afforded by CM, whereas it was ineffective in AM hearts. PKC inhibition with chelerythrine was ineffective in CM hearts while completely abrogating AM preconditioning. Moreover, whereas beta(1)-AR blockade with CGP-20712A failed to alter recovery in CM hearts, the beta(2)-AR antagonist ICI-118,551 significantly attenuated postischemic recovery. These data describe novel findings whereby CM preconditioning is mediated by a PKC-independent pathway involving PKA, beta(2)-AR, and G(s) proteins, whereas AM preconditioning is mediated via G(i) proteins and PKC.
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PMID:Cardioprotective effects of acute and chronic opioid treatment are mediated via different signaling pathways. 1673 54

Endocrine-disrupting compounds (EDCs) may interfere with neuronal development due to high levels of accumulation in biological tissue and potentially aberrant steroid signaling. Treatment of dissociated embryonic Xenopus spinal cord neurons with the EDC, nonylphenol (NP), did not alter cell survival or neurite outgrowth but inhibited neurotrophin-induced neurite outgrowth, effects that were recapitulated by treatment with comparable concentrations of 17 beta-estradiol (E2) and beta-estradiol 6-(O-carboxy-methyl)oxime: BSA (E2-BSA), but not a synthetic androgen. Effects of NP were not inhibited by the nuclear estrogen receptor antagonist, ICI 182,780, but were inhibited by the G protein antagonist, pertussis toxin. Nerve growth factor (NGF)-induced neurite outgrowth in Xenopus neurons was shown to require MAPK signaling. NP did not affect TrkA expression, MAPK signaling, or phosphatidylinositol 3' kinase-Akt-glycogen synthase kinase 3 beta (PI3K-Akt-GSK3 beta) signaling in Xenopus. The ability of NP to inhibit NGF-induced neurite outgrowth without altering survival was recapitulated in the rat pheochromocytoma (PC12) cell line. As with Xenopus neurons, the inhibitory actions of NP in PC12 cells were not antagonized by ICI 182,780 and did not involve alterations in signaling along either the MAPK or PI3K-Akt-GSK3 beta pathways. NP did significantly inhibit the ability of NGF to increase protein kinase A activity in this cell line. These data have important implications with respect to potentially deleterious effects of NP exposure during early neural development and highlight the fact that bioaccumulation of EDCs, such as NP, may elicit very disparate effects along divergent signaling pathways than those that arise from the actions of physiological levels of endogenous estrogens.
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PMID:The endocrine-disrupting compound, nonylphenol, inhibits neurotrophin-dependent neurite outgrowth. 1677 73

We recently reported that soy isoflavones increase gene expression of endothelial nitric-oxide synthase (eNOS) and antioxidant defense enzymes, resulting in improved endothelial function and lower blood pressure in vivo. In this study, we establish that equol (1-100 nM) causes acute endothelium- and nitric oxide (NO)-dependent relaxation of aortic rings and rapidly (2 min) activates eNOS in human aortic and umbilical vein endothelial cells. Intracellular Ca2+ and cyclic AMP levels were unaffected by treatment (100 nM, 2 min) with equol, daidzein, or genistein. Rapid phosphorylation of ERK1/2, protein kinase B/Akt, and eNOS serine 1177 by equol was paralleled by association of eNOS with heat shock protein 90 (Hsp90) and NO synthesis in human umbilical vein endothelial cells, expressing estrogen receptors (ER)alpha and ERbeta. Inhibition of phosphatidylinositol 3-kinase and ERK1/2 inhibited eNOS activity, whereas pertussis toxin and the ER antagonists ICI 182,750 and tamoxifen had negligible effects. Our findings provide the first evidence that nutritionally relevant plasma concentrations of equol (and other soy protein isoflavones) rapidly stimulate phosphorylation of ERK1/2 and phosphatidylinositol 3-kinase/Akt, leading to the activation of NOS and increased NO production at resting cytosolic Ca2+ levels. Identification of the nongenomic mechanisms by which equol mediates vascular relaxation provides a basis for evaluating potential benefits of equol in the treatment of postmenopausal women and patients at risk of cardiovascular disease.
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PMID:The isoflavone Equol mediates rapid vascular relaxation: Ca2+-independent activation of endothelial nitric-oxide synthase/Hsp90 involving ERK1/2 and Akt phosphorylation in human endothelial cells. 1684 Jul 83

Although estrogen replacement has been the main therapy to prevent and treat osteoporosis, there are concerns about its safety. Phytoestrogens have attracted attention to their potential impacts in osteoporosis prevention and treatment. Among phytoestrogens, the isoflavone daidzein (Dz) acts on transcription via the intracellular estrogen receptors (ER), mainly ERbeta, in osteoblasts, but mimics only part of the estrogen effects. Since estradiol also exerts rapid effects in osteoblasts, we investigated the multistep processes involved in the rapid actions of low (1-100 pM) doses of daidzein. Dz bound to a membrane moiety, related to ERbeta since the calcium response to Dz was blocked by an anti-ERbeta antibody directed against the C-terminus, but not by a double-stranded siRNA specific for ERbeta. This protein was coupled to a pertussis toxin (PTX)-sensitive Gbeta1 subunit whose transducer was PLC-beta2, which triggered a rapid (5 sec) mobilization of calcium from the endoplasmic reticulum. Dz phosphorylated within 15 sec ERK1/2 whose phosphorylation involved two routes: Gbeta1/PLC-beta2/PKC/c-Raf-1/MEK1/2 and Gbeta1/PI3K/cSrc/c-Raf-1/MEK1/2 as shown using several inhibitors. Dz induced rapid (1 min) changes in the actin cytoskeleton via the two routes. The rapid (20 sec) phosphorylation of Elk-1 and CREB by Dz involved Gbeta1 and ERK1/2. All the processes were insensitive to the estradiol antagonist ICI 182,780. In conclusion, the rapid effects of Dz seem to be biologically relevant for the function of osteoblast in bone since the isoflavone activates transcription factors linked to early genes controlling cellular proliferation and differentiation, and modulates actin cytoskeleton which controls cell adhesion, division, or secretion.
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PMID:Signaling networks from Gbeta1 subunit to transcription factors and actin remodeling via a membrane-located ERbeta-related protein in the rapid action of daidzein in osteoblasts. 1697 65

Stimulation of cardiac beta-adrenergic receptors (beta-AR) activates both the G(s)- and G(i)-coupled signaling cascades, including the phosphoinositide 3 kinase (PI3K) pathway, that have important physiological implications. Multiple isoforms of PI3K exist in the heart. The goals of this study were to examine the intracellular signaling pathways linking beta-AR to PI3K and to identify the PI3K isoform mediating this transactivation in a cardiac context. Acute beta-AR stimulation with isoproterenol resulted in increased tyrosine kinase-associated PI3K activity and phosphorylation of Akt and p70S6K in H9c2 cardiomyocytes. Cotreatment with ICI-118,551, but not CGP-20712, abolished the increase in PI3K activity, suggesting a beta(2)-AR-mediated event. PI3K activation was also abrogated by cotreatment with pertussis toxin, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2, a selective Src-family tyrosine kinases inhibitor), or AG-1296 [selective platelet-derived growth factor receptor (PDGFR) inhibitor] but not with an inhibitor for protein kinase A, protein kinase C, Ras, adenylyl cyclase, epidermal growth factor receptor, or insulin-like growth factor-1 receptor. beta-AR stimulation induced an increase in tyrosine phosphorylation of PDGFR, which was abolished by inhibition of Src either by PP2 or small interfering RNA. Moreover, H9c2 cardiomyocytes stably transfected with a vector expressing a Gbetagamma sequestrant peptide derived from the COOH-terminus of beta-AR kinase-1 failed to activate PI3K after beta-AR stimulation, suggesting Gbetagamma is required for the transactivation. Furthermore, acute beta-AR stimulation in vivo resulted in increases in PDGFR-associated PI3K and PI3Kalpha isoform activities but not the activities of other isoforms (PI3Kbeta, -delta, -gamma) in adult mouse heart. Taken together, these data provide in vitro and in vivo evidence for a novel mechanism of beta-AR-mediated transactivation of cardiac PI3Kalpha via sequential involvement of Galpha(i)/Gbetagamma, Src, and PDGFR.
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PMID:A novel signaling pathway for beta-adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes. 1736 56

The classical view of the molecular actions of estrogen is described by its interaction with the intracellular estrogen receptor (ER), the binding of hormone receptor complex to the estrogen response element (ERE) on the DNA and followed by the alterations of gene expressions. Recently it has been reported that membrane estrogen receptor (mER) exist and it is suggested to be G protein linked receptor. In this report we show that under steroid-free culture conditions supplemented with low percentage of charcoal-stripped serum, differential estrogen treatments of human breast cancer MCF7 cells induce different responses of cyclic AMP (cAMP) productions. Treating [2-(3)H]adenine-labeled MCF7 cells with 1 nM estrogen for 30 min stimulates cAMP production by measuring the ratio of [3H]cAMP:Total [3H]adenine nucleotides (ATP+ADP+cAMP), as determined by column chromatography, when compared with the control. This short-term estrogen treatment also significantly enhanced forskolin stimulated cAMP production when compared with the ratio of cAMP/Total measured in cells stimulated with forskolin alone. Pre-treating MCF7 cells with the same concentration of estrogen for 24h before the assay, on the contrary, significantly decreased the basal cAMP level and it also suppressed cAMP production stimulated with forskolin when compared with its respective value under short-term estrogen treatment. Estrogen receptor antagonist ICI 182780 abolished both the stimulatory and suppressive effect of estrogen on cAMP synthesis indicating both effects were mediated through ER. Pre-treating cells with pertussis toxin relieved the suppression of cAMP synthesis by chronic estrogen treatment. Our data suggest that estrogen exerts differential effects on the cAMP production in MCF7 cells, involving the activations Galpha(i) and Galpha(s) family of G proteins, depending on the length of time of hormone treatment.
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PMID:Differential regulation of cyclic AMP synthesis by estrogen in MCF7 cells. 1788 71

Although beta(2)-adrenoceptors represent 15-25% of beta-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of beta(2)-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, -5% at 60 nM) followed by a moderate positive inotropic effect (+36% at 6 microM) due to activation of beta(1)-adrenoceptors. In the presence of 4 microM atenolol, the concentration-dependent NIE (-12% at 6 microM) was biphasic, best described by a double logistic equation with respective EC(50) values of 3 and approximately 420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/cytosolic phospholipase A(2) (cPLA(2)) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA(2). The possibility that these effects are due to an equilibrium between different affinity states of the receptor (G(s)/G(i) coupled and G(i) independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that beta(2)-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.
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PMID:Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of beta2-adrenoceptor agonists in guinea pig right papillary muscles. 1794 37


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