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)

Dose-effect curves were generated for the cannabinoids [intracerebroventricularly (icv.)] and compared with those previously generated after administration intrathecally (i.t.). The ED50 values after administration of levonantradol, CP 55,940, delta 9-THC and delta 8-THC i.t. vs. icv. did not differ significantly. CP 56,667 was significantly more potent after icv. administration than i.t. administration, and was nearly 10 times more potent than CP 55,940 (icv.). CP 55,940 and CP 56,667, which did not produce greater than additive effects in combination with morphine when the drugs were administered i.t., shifted the morphine (icv.) dose-effect curve in a parallel manner nearly 10-fold after icv. administration. The antinociceptive effects of the cannabinoids (icv.) were not blocked by ICI 174,864 (20 micrograms/mouse), nor-BNI (70 micrograms/mouse) or naloxone (20 micrograms/mouse or 10 mg/kg s.c.). Pertussis toxin pretreatment i.t. for 7 days totally abolished the antinociception produced by the cannabinoids (icv. and i.t.). Pretreatment of the mice with forskolin (i.t.) or Cl-cAMP (10 micrograms/mouse i.t.), which produced no antinociception, significantly attenuated the antinociception produced by the delta 9-THC and CP 55,940. However, when administered icv., forskolin and Cl-cAMP produced antinociception, but did not block or produce greater than additive effects with the antinociception produced by the cannabinoids administered icv. The i.t. administration of calcium and calcium modulators failed to alter the antinociception produced by the i.t. administration of the cannabinoids. Conversely, calcium (icv.) blocked the antinociceptive effects of the cannabinoids. The AD50 values (+/- CL) for calcium-induced block of delta 9-THC, delta 8-THC and CP 55,940 were 215 (94-489), 176 (122-253) and 123 (81-186) nmol/mouse, respectively. omega-Conotoxin (1 micrograms/mouse icv.), which did not alter the antinociceptive effects of delta 9-THC, significantly reversed the calcium-induced blockade of delta 9-THC. Thapsigargin (icv.) blocked the antinociception produced by delta 9-THC and CP 55,940. Apamin, blocker calcium-gated potassium channels, produced a parallel rightward shift in the dose-effect curves of delta 9-THC, delta 8-THC and CP 55,940 (i.t.). However, apamin (5 ng/mouse icv.) failed to block icv. administered cannabinoids. Because acute administration of opiates/opioids have been shown to interact with Gi/o protein-coupled receptors, decrease calcium entry to and content of neurons, reduce cAMP levels and produce hyperpolarization of neurons via both ATP- and apamin-sensitive potassium channels, these three intracellular systems may be common points of interaction with the cannabinoids.
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PMID:Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine. 781 46

Recently we demonstrated that the effects of beta 2-adrenoceptor (AR) stimulation to augment Ca2+ current (ICa), cytosolic Ca2+ (Cai) transients, and contractility in rat ventricular myocytes are largely dissociated from its effect to increase cellular cAMP levels. This result suggested that beta 2ARs might be coupled to signaling pathways other than the Gs alpha-mediated activation of adenylyl cyclase. Here we show that pertussis toxin (PTX) pretreatment specifically potentiates the responses of rat heart cells to beta 2AR but not beta 1AR stimulation. After PTX pretreatment, 1) the dose-response curve for the effects of the beta 2AR agonist zinterol on contraction amplitude is shifted leftward and upward (EC50 changed from about 1.0 microM to 70 nM), 2) in indo-1-loaded cells, the maximal effects of zinterol (10(-5) M) on Cai transient and contraction amplitudes are additionally increased 1.7- and 2.0-fold, respectively, over those in control cells, and 3) the increase in ICa amplitude induced by the same zinterol concentration is potentiated by 2.5-fold. Similar effects of PTX are observed when beta 2ARs are stimulated by isoproterenol in the presence of a selective beta 1AR blocker, CGP 20712A. All effects of beta 2AR agonists in both PTX-treated and control cells are abolished by a selective beta 2AR blocker, ICI 118,551. In contrast, neither the base-line ICa, Cai transient, and contraction in the absence of beta AR stimulation nor the beta 1AR-mediated augmentations of these parameters are significantly altered by PTX treatment. These results demonstrate, for the first time, that the Gs-coupled beta 2AR can simultaneously activate a pathway that leads to functional inhibition in cardiac cells via a PTX-sensitive G protein. The activation of more than one G protein during beta 2AR stimulation, leading to functionally opposite effects, may provide a mechanism to protect the heart from Ca2+ overload and arrhythmias during the response to stress.
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PMID:Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. 787 40

The effect of left ventricular hypertrophy (LVH) due to chronic pressure overload on right atrial (RA) and left ventricular (LV) myocardial beta-adrenergic receptor (beta-AR) density and subtypes, adenylyl cyclase (AC) activity and ADP-pertussis toxin ribosylated proteins was investigated in humans with LVH due to aortic stenosis and in patients without LVH undergoing heart surgery for mitral stenosis or coronary artery disease taken as controls. Both groups presented normal systolic function or plasma catecholamine levels. In LVH and controls, beta-AR density was similar in RA (62 +/- 6 vs 77 +/- 12 fmol.mg-1 protein) and LV (39 +/- 7 vs 32 +/- 2 fmol.mg-1 protein). In LVH, beta 1-AR percentage was < than in controls in LV (35 +/- 11 vs 73 +/- 5%, P < 0.05) but not in RA (79 +/- 5 vs 73 +/- 8%). Basal AC activity in RA (19 +/- 4 vs 21 +/- 6 pmol.mg-1 protein) and LV (22 +/- 5 vs 27 +/- 3 pmol.mg-1 protein) was similar in LVH and in controls. Isoprenaline-induced stimulation of AC in RA was similar in LVH and in controls (51 +/- 18 vs 36 +/- 18%) but < in LV of LVH (7 +/- 6 vs 45 +/- 6%, P < 0.05). In the presence of ICI-118,551 (a beta 2-adrenoceptor antagonist), isoprenaline failed to induce any increase in cAMP in LVH. The quantification of ADP-pertussis toxin ribosylated proteins indicated a lower concentration of substrates in LV myocardial membranes from LVH. These data indicate that in LVH due to pressure overload, there is a down-regulation of beta 1-AR and an increase in beta 2-AR density. This is associated with alterations of the transmembrane signalling marked by a decreased capacity of isoprenaline to stimulate AC and an impaired expression of Gi proteins.
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PMID:Cardiac beta-adrenoceptors and adenylyl cyclase activity in human left ventricular hypertrophy due to pressure overload. 818 1

The goal of this study was to characterize further the manner in which the peptide leukotriene (LT) D4 evokes endothelium-dependent relaxation of the canine renal vein (RV) and artery (RA). The effects of four chemically and structurally dissimilar LT receptor antagonists and pertussis toxin (PTX), on LTD4-evoked relaxation of RV and RA rings, were determined and compared. In the presence of ICI 198,615 (10(-5) M), relaxation of both the RA and RV evoked by LTD4 was markedly attenuated. MK-571 (10(-5) M) altered neither RA nor RV relaxation evoked by LTD4. Relaxation of the RV but not the RA, evoked by LTD4, was attenuated in the presence of LY171,883 (10(-5) M). L649,923 (10(-5) M) solely inhibited LTD4-evoked relaxation of the RA. Pretreatment of vascular rings with PTX (250 ng/ml) for 2 h attenuated the vasomotor relaxation evoked by LTD4 in the RA but not in the RV. These observations suggest that LTD4-evoked relaxation of the RA and RV is dependent on different mechanisms. The endothelium-dependent response produced in the RA apparently involves a PTX-sensitive G protein. It is proposed that multiple signal transduction pathways and perhaps different LTD4 receptors may account for the diverse activity of LTD4.
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PMID:Antagonism of LTD4-evoked relaxation in canine renal artery and vein. 821 35

Previous studies have established that the delta-selective antagonist ICI-174,864 exhibits negative intrinsic activity at the delta-opioid receptors in NG108-15 membranes. To determine whether ICI-174,864 can function as a true inverse agonist in intact cells, its ability to stimulate cAMP accumulation was examined in a human embryonic kidney 293 cell line (293/DOR) expressing the cloned murine delta-opioid receptor. Forskolin-stimulated cAMP accumulation in the 293/DOR cells was dose-dependently suppressed by the delta-selective agonist [D-Pen2, D-Pen5]enkephalin, and such inhibition was abolished by pertussis toxin or the opiate antagonist naloxone. In contrast, ICI-174,864 significantly potentiated the forskolin response. The ICI-174,864-induced enhancement of the forskolin response exhibited dose-dependency and was antagonized by [D-Pen2,D-Pen5]enkephalin and blocked by pertussis toxin. Neither ICI-174,864 nor pertussis toxin elevated the basal level of cAMP accumulation in the absence of forskolin. Other opiate antagonists, such as naloxone and naltrindole, were ineffective in enhancing the forskolin-stimulated cAMP accumulation. Elevation of cAMP levels in response to the activation of Gs (through either ligand-bound receptor or point mutation on alpha(s)) was also potentiated by ICI-174,864. Our results indicate that ICI-174,864 behaves as an inverse agonist in human embryonic kidney 293 cells stably expressing the delta-opioid receptor. The inverse agonistic effect of ICI-174,864 seemed to require Gi proteins and was clearly manifested when adenylyl cyclase was activated.
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PMID:Inverse agonistic effect of ICI-174,864 on the cloned delta-opioid receptor: role of G protein and adenylyl cyclase activation. 896 89

A nonisotopic, immunoelectrophoretic technique was used to analyze the characteristics of opioid-evoked activation of Gi2/ G(x/z) transducer proteins of mouse periaqueductal gray matter membranes. In the presence of picomolar concentrations of guanosine 5'-O-(3-thiotriphosphate), the opioid agonists promoted concentration-dependent increases of immunoreactivity associated with free Gi2alpha and G(x/z)alpha subunits. [D-Ala2,N-MePhe4, Gly-ol5]enkephalin and morphine (preferential agonists at mu opioid receptors) and beta-endorphin-(1-31) (an agonist at mu/delta opioid receptors) activated G(x/z) proteins. In contrast, the agonists of delta opioid receptors, [D-Ala2]deltorphin II and [D-Pen(2,5)]enkephalin, displayed little or no activity on this pertussis toxin resistant regulatory protein. Although exhibiting diverse efficacy, all the opioids studied activated Gi2 transducer proteins. [D-Ala2,N-MePhe4,Gly-ol5]enkephalin and [D-Ala2]-deltorphin II were more potent at Gi2alpha subunits than at G(x/z)alpha subunits. The opioid antagonist naloxone displayed a competitive profile in reducing the activation of G proteins promoted by morphine. Moreover, [D-Pen(2,5)]enkephalin antagonized the releasing effect exerted by [D-Ala2]deltorphin II on Gi2alpha and G(x/z)alpha subunits. N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI-174864) reduced the G alpha-related immunosignals promoted by agonists of delta opioid receptors. Therefore, it is suggested that opioids exhibit marked differences in efficacy and/or potency in the activation of Gi2 and G(x/z) transducer proteins in mouse periaqueductal gray matter.
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PMID:Opioids binding mu and delta receptors exhibit diverse efficacy in the activation of Gi2 and G(x/z) transducer proteins in mouse periaqueductal gray matter. 910 43

We evaluated whether Gi has a tonic inhibitory influence on myocardial adenylate cyclase (AC) in an agonist-independent way, and, if so, whether this is attributable to substantial coupling between agonist-free, empty inhibitory receptors and G. Rabbits received pertussis toxin (PTX, 10 micrograms/kg i.v.) 40 h before preparing ventricular myocardial membranes, which was associated with virtually complete in vivo ADP-ribosylation and inactivation of the 41-kDa substrate. Pretreatment with PTX had no influence on basal AC activity but significantly enhanced AC activity elicited by 100 microM GTP. Furthermore, it markedly increased AC activity stimulated with 5'-guanylyl imidodiphosphate (GppNHp) and isoproterenol through a wide range of concentrations of these stimulants. These findings indicate that Gi has a tonic influence on he stimulatory effects of guanine nucleotides and beta-adrenoceptor stimulation on AC even in the absence of the inhibitory receptor agonists. The muscarinic receptor antagonists atropine and AF-DX 116 significantly enhanced isoproterenol-stimulated AC activity, as PTX pretreatment did, except that statistically significant increasing effects of these antagonists on GppNHp-stimulated AC activity was observed only at higher concentrations of GppNHp. The enhancement by atropine was not detected in PTX-pretreated membranes. The selective beta 2-adrenoceptor antagonist ICI 118,551 did not modify the stimulatory effects of guanine nucleotides and isoproterenol on AC in either control or PTX-pretreated membranes, excluding the possible involvement of beta 2-adrenoceptors in tonic activation of Gi. We conclude that Gi is tonically activated by agonist-free, empty muscarinic receptors, which leads to attenuation of Gs-mediated or beta-adrenoceptor-mediated activation of AC. The potentiating effect of PTX pretreatment on GppNHp-stimulated AC activity may be at least partially due to the direct action of PTX on the Gi heterotrimeric complex, independently of the coupled receptors.
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PMID:Agonist-independent tonic inhibitory influence of Gi on adenylate cyclase activity in rabbit ventricular myocardium and its removal by pertussis toxin: a role of empty receptor-mediated Gi activation. 914 Aug 33

The ability of the delta opioid agonist DPDPE ([D-Pen2, D-Pen4]enkephalin) to stimulate binding of the GTP analog guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) to pertussis toxin-sensitive G proteins has been characterized in membranes from NG108-15 mouse neuroblastoma X rat glioma cells. The presence of GDP, or its hydrolysis-resistant analog GDPbetaS, and Mg++ ions was essential to observe agonist-mediated stimulation of [35S]GTPgammaS binding, although the guanine dinucleotides alone had complex inhibitory and stimulatory effects on [35S]GTPgammaS binding. The relative ability of the delta antagonists benzylidenenaltrexone and naltriben to inhibit DPDPE-stimulated [35S]GTPgammaS binding suggested the opioid receptor involved was of the delta-2 subtype. Ligand binding assays demonstrated biphasic binding of these antagonists to this single receptor type. [35S]GTPgammaS binding was also stimulated by [D-Ser2,Leu5,Thr6]enkephalin > deltorphin II = DPDPE = etorphine > levallorphan = diprenorphine = nalorphine = naltrindole. The delta antagonists benzylidenenaltrexone, TIPP (Tyr-Tic-Phe-Phe) and naltriben had no effect, but ICI 174864 (N, N-diallyl-Tyr-Aib-Phe-Leu-OH) acted as an inverse agonist and inhibited [35S]GTPgammaS binding. Pertussis toxin pretreatment blocked agonist stimulation of [35S]GTPgammaS binding and also reduced basal binding, thus confirming the presence of constitutively active delta receptors. Replacement of Na+ in the assay buffer with K+ afforded an increased level of basal [35S]GTPgammaS binding and an apparent increase in both the inverse agonist activity of ICI 174864 and the agonist activity of the partial agonist diprenorphine relative to the full agonist [D-Ser2, Leu5,Thr6]enkephalin. The stimulation of [35S]GTPgammaS binding to NG108-15 cell membranes allows a functional measure of delta opioid activity that can provide systems of differing relative efficacy.
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PMID:Delta opioid modulation of the binding of guanosine-5'-O-(3-[35S]thio)triphosphate to NG108-15 cell membranes: characterization of agonist and inverse agonist effects. 940 3

The delta(delta)-opioid agonists [D-Pen2,5]enkephalin (DPDPE) and [D-Ala2]deltorphin II increased the formation of inositol phosphates (IPs) in mice periaqueductal gray matter (PAG) slices pre-labeled with myo-[3H]inositol. Both delta-agonists caused an increase in IP accumulation in a dose-dependent manner (1-100 microM) and which was pertussis toxin (0.5 microg/mouse, i.c.v.) sensitive. This effect was blocked by the delta-antagonist ICI-174.864 (10 microM). The presence of subtypes of the delta-opioid receptor (delta1 and delta2) in PAG has been suggested by pharmacological studies. In this brain structure, naltrindrole 5'-isothiocyanate (5'-NTII), but not 7-benzylidenenaltrexone (BNTX), antagonized the effects of DPDPE and [D-Ala2]deltorphin II, suggesting the involvement of a population of delta receptors sensitive to the delta2-antagonist NT II on this effect. To further investigate the participation of delta-receptor subtypes in the stimulation of IPs formation, mice were injected with antisense oligodeoxynucleotides (ODNs) directed to nucleotides 7-26 or 2946 of the cloned delta-receptor mRNA, and PAG slices from these animals were used in in vitro assays. The results demonstrate that the reported increase of phosphoinositide (PI) hydrolysis depends on the agonist activation of the delta2-opioid receptor subtype in the PAG.
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PMID:The delta2-opioid receptor subtype stimulates phosphoinositide metabolism in mouse periaqueductal gray matter. 958 72

Astrocytes in primary culture from rat cerebral cortex were probed concerning the expression of delta-opioid receptors and their coupling to changes in intracellular free calcium concentrations ([Ca2+]i). Fluo-3 or fura-2 based microspectrofluorometry was used for [Ca2+]i measurements on single astrocytes in a mixed astroglial-neuronal culture. Application of the selective delta-opioid receptor agonist, [D-Pen2, D-Pen5]-enkephalin (DPDPE), at concentrations ranging from 10 nM to 100 microM, induced concentration-dependent increases in [Ca2+]i (EC50 = 114 nM). The responses could be divided into two phases, with an initial spike in [Ca2+]i followed by either oscillations or a sustained elevation of [Ca2+]i. These effects were blocked by the selective delta-opioid receptor antagonist ICI 174864 (10 microM). The expression of delta-opioid receptors on astroglial cells was further verified immunohistochemically, using specific antibodies, and by Western blot analyses. Pre-treatment of the cells with pertussis toxin (100 ng/ml, 24 h) blocked the effects of delta-opioid receptor activation, consistent with a Gi- or Go-mediated response. The sustained elevation of [Ca2+]i was not observed in low extracellular Ca2+ and was partly blocked by nifedipine (1 microM), indicating the involvement of L-type Ca2+ channels. Stimulating neurons with DPDPE resulted in a decrease in [Ca2+]i, which may be consistent with the closure of the plasma membrane Ca2+ channels on these cells. The current results suggest a role for astrocytes in the response of the brain to delta-opioid peptides and that these opioid effects in part involve altered astrocytic intracellular Ca2+ homeostasis.
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PMID:Delta-opioid receptors on astroglial cells in primary culture: mobilization of intracellular free calcium via a pertussis sensitive G protein. 968 28


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