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)

Opioid agonists selective for mu-, delta-, and kappa-receptors are all capable of regulating the stimulated release of noradrenaline from three terminal fields (cortex, hippocampus, and cerebellum) of the noradrenergic projections from locus coeruleus in the guinea pig brain. Intracerebroventricular injections of pertussis toxin abolished the ability of a mu-selective agonist and of a delta-selective agonist to inhibit stimulated noradrenaline release, but left unaffected the concentration-related inhibition of NE release by a kappa agonist. Thus, mu- and delta-receptors have been shown to be coupled to their effector system in these noradrenergic neurons via guanyl nucleotide binding proteins (G proteins) which are sensitive to pertussis toxin, while kappa-receptors in the same neurons appear to be coupled through a different mechanism which is significantly less sensitive to pertussis toxin. In contrast to opioid receptor regulation of noradrenaline release in guinea pig hippocampus, mu-, but not delta- or kappa-agonists are capable of regulation of stimulated noradrenaline release from rat hippocampus and cortex, and kappa-, but not mu- or delta-agonists are capable of inhibiting the stimulated release of dopamine from rat striatum and cortex. Pertussis toxin injections significantly attenuated mu-agonist inhibition of noradrenaline release, but had no effect on the ability of a kappa-selective agonist to regulated dopamine release, confirming the insensitivity of the kappa-receptor-effector coupling system to pertussis toxin.
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PMID:Effects of pertussis toxin on opioid regulation of catecholamine release from rat and guinea pig brain slices. 254 29

Stimulation-induced noradrenaline (NA) release in rabbit hippocampus is inhibited by activation of presynaptic alpha 2-adrenoceptors and kappa-opioid receptors. The purpose of the present study was to investigate (a) an interference between the alpha 2- and kappa-mechanisms, and (b) a coupling of the opioid receptors to pertussis toxin (PT)-sensitive guanine nucleotide-binding proteins (G proteins), as has been previously shown for the alpha 2-receptors. [3H]NA release from hippocampal slices was evoked by electrical field stimulation (360 pulses/3 Hz). Inhibition of stimulation-evoked NA release by the preferential kappa-receptor agonist ethylketocyclazocine (EKC) was increased in the presence of the alpha 2-adrenoceptor antagonist yohimbine (0.1 or 1.0 microM). When autoinhibition was completely removed, EKC (1 microM) almost abolished transmitter release. Pretreatment of hippocampal tissue with either PT (8 micrograms/ml; 18 h) or N-ethylmaleimide (NEM) (30 microM; 30 min), which has been shown to alkylate PT substrates, diminished the EKC-produced inhibition of NA release. The kappa-mechanism was still impaired by these compounds when the alpha 2-receptors were blocked with yohimbine. An effect of NEM on the active site of the kappa-receptor seems to be unlikely, because NEM diminished the EKC-induced inhibition of release irrespective of whether or not the opioid receptor was occupied by EKC during exposure to NEM. The present results suggest an interference of both alpha 2- and kappa-opioid receptor-coupled signal transduction possibly through competition for a common pool of G proteins.
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PMID:Presynaptic kappa-opioid receptors on noradrenergic nerve terminals couple to G proteins and interact with the alpha 2-adrenoceptors. 255 17

A mu-opioid receptor-GTP binding protein (mu-opioid receptor-G-protein) complex from the 7315c cell was solubilized with CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate) and reconstituted into phospholipid vesicles. Pretreatment of the tissue with either [3H]etorphine or morphine greatly improved recovery of the receptor and maintained it in a GTP-sensitive state. GTP sensitivity was consistent with the hypothesis that a receptor-G-protein complex had been obtained. Other evidence consistent with this hypothesis was that recovery of the solubilized, prelabelled receptor was decreased by approximately 70% by pretreatment of 7315c cells with pertussis toxin. The reconstituted receptor was mu-selective: DAGO (Tyr-D-Ala-Gly-Met-Phe- NH(CH2)2OH), but not ICI 174864 or U50488-H, displaced [3H]etorphine binding with high affinity. The affinity of the reconstituted receptor for [3H]etorphine (1.25 +/- 0.20 nM) was similar to that observed for the membrane-associated receptor (0.53 +/- 0.25 nM). GTP gamma S decreased this affinity 3-fold without changing the number of binding sites. The potencies of GTP gamma S and GTP in diminishing [3H]etorphine binding were similar in the membrane and vesicle preparations, but were 10-fold lower than the potencies observed in diminishing binding to the solubilized receptor. The ability to reconstitute a functional mu-opioid receptor-G-protein complex will facilitate further study of the structure and function of the receptor and the specific identification of the associated GTP-binding protein(s).
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PMID:Reconstitution of the solubilized mu-opioid receptor coupled to a GTP-binding protein. 255 7

Studies with the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum were undertaken to investigate the relationship between guanine nucleotide-binding proteins (G-proteins) and chronic opioid receptor activation in vivo. Treatment with the narcotic agonist fentanyl, at doses which render the preparation tolerant and dependent, led to an increase of pertussis toxin-catalysed incorporation of ADP-ribose in a protein of approximately 40,000 mol. wt. Quantitative immunoblotting, using site-directed antisera, demonstrated an upregulation of G alpha i/G alpha o and, to an even greater degree, of G beta. However, the level of G alpha s was decreased by the same treatment. All alterations observed were abolished by the concomitant presence of the antagonist naloxone. The implications of this differential regulation of G-protein subunits for opiate-induced tolerance and dependence are discussed.
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PMID:Chronic opiate receptor activation in vivo alters the level of G-protein subunits in guinea-pig myenteric plexus. 255 43

The intradermal injection of mu (morphine, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and morphiceptin), kappa (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneactemide) and delta ([D-Pen2.5]-enkephalin and [D-Ser2]-[Leu]enkephalin-Thr) selective opioid-agonists, by themselves, did not significantly affect the mechanical nociceptive threshold in the hindpaw of the rat. Intradermal injection of mu, but not delta or kappa opioid-agonists, however, produced dose-dependent inhibition of prostaglandin E2-induced hyperalgesia. The analgesic effect of the mu-agonist morphine was dose-dependently antagonized by naloxone and prevented by co-injection of pertussis toxin. Morphine did not, however, alter the hyperalgesia induced by 8-bromo cyclic adenosine monophosphate. We conclude that the analgesic action of opioids on the peripheral terminals of primary afferents is via a binding site with characteristics of the mu-opioid receptor and that this action is mediated by inhibition of the cyclic adenosine monophosphate second messenger system.
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PMID:Involvement of the mu-opiate receptor in peripheral analgesia. 255 56

Stimulation of NG115-401L neuronal cells with bradykinin produces a dose-dependent increase in inositol phosphate production which is not blocked, rather slightly increased, after treatment with pertussis toxin. Nevertheless, pertussis toxin stimulates ADP-ribosylation of a 41K membrane protein, and blocks opioid receptor-mediated inhibition of stimulated cAMP production in these cells. These results suggest that bradykinin responses in the NG115-401L cells are pertussis-insensitive, unlike bradykinin responses reported in other neuronal cell lines.
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PMID:Bradykinin stimulation of inositol phosphate and calcium responses in insensitive to pertussis toxin in NG115-401L neuronal cells. 282 11

Multiple affinity states of opioid receptors of the mu and delta types have been identified in membranes prepared from cells which bear only one type of opioid receptor (mu receptors in 7315c cells, delta receptors in NG 108-15 cells), and in guinea pig cortical membranes where both types of receptors were present in the membrane preparations. States of mu and delta receptors which have agonist affinities too low to be identified by radiolabeled agonist have been measured indirectly by agonist competition for sites labeled by radioactive antagonist. Using analogues of guanyl nucleotides, we have examined the competition of the mu and delta agonists DAGO and DSLET against [3H]DIP or [3H]NAL binding to opioid receptors and identified several agonist affinity states. In the absence of added nucleotide, competition of DSLET for [3H]DIP binding to delta opioid receptors revealed the presence of two binding sites with differing apparent agonist affinities. Addition of GDP beta S produced a steep monophasic curve which was best fit by a one-site model. In contrast, in the presence of added GTP or GTP gamma S, two affinity states were again apparent for DSLET competition at the delta receptor. The competition curve with GTP was shifted to the right relative to that produced in the absence of added guanyl nucleotide, indicating the presence of a lower apparent affinity state than any observed under other treatment conditions. DAGO competed against [3H]DIP or [3H]NAL binding to mu receptors over a wide concentration range in the absence of added guanyl nucleotide, consistent with the occupation by this ligand of more than one agonist affinity state of the mu receptor. However, when GDP beta S was added to the incubation mixture, only a single binding site was identified. Two mu receptor affinity states were again observed in the presence of added GTP or GTP gamma S. One of these had significantly lower apparent affinity than those states detected in the absence of added nucleotide or with GDP beta S. Pertussis toxin treatment resulted in a monophasic agonist competition curve which was best fitted by a single-site model in both 7315c and NG108-15 cell membranes. Addition of 100 microM GTP did not affect the agonist Kapp or Bmax after pertussis toxin treatment, suggesting that sites labeled under these conditions were not functionally associated with a G protein. In general, the effects of guanyl nucleotides were qualitatively similar at mu and delta receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple agonist-affinity states of opioid receptors: regulation of binding by guanyl nucleotides in guinea pig cortical, NG108-15, and 7315c cell membranes. 283 86

Pertussis toxin-catalyzed ADP-ribosylation of the guanine nucleotide-binding proteins Gi and Go is shown to proceed in Mg2+-digitonin extracts from rat brain; the Mr 41,000 and Mr 39,000 peptides are labelled there as in the membranes. The ADP-ribosylation in detergent solution retains the differential sensitivity to guanine nucleotide analogues. This reaction also removes the partial inhibition by the guanine nucleotides of the binding of opioid agonists, as does the same treatment in the membranes. The partial inhibition of agonist binding by Na+, however, is left unchanged. The binding of the antagonist naloxone is little affected by Na+ or by guanine nucleotides in the treated membranes, but the treated soluble receptors show an enhanced binding in high-Na+ medium, although still guanine nucleotide insensitive. The data suggest that the toxin reaction in the absence of guanine nucleotides and agonist stabilizes the opioid receptor in a receptor-G-protein coupled state which is no longer sensitive to guanine nucleotides but retains its sensitivity to the Na+ ions.
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PMID:ADP-ribosylation with pertussis toxin modulates the GTP-sensitive opioid ligand binding in digitonin-soluble extracts of rat brain membranes. 283 32

The target size for opioid receptor binding was studied after manipulations known to affect the interactions between receptor and GTP-binding regulatory proteins (G-proteins). Addition of GTP or its analogs to the binding reaction, exposure of intact cells to pertussis toxin prior to irradiation, or treatment of irradiated membranes with N-ethylmaleimide did not change the target size (approximately equal to 100 kDa) for opioid receptors in NG 108-15 cells and rat brain. These data suggest that the 100-kDa species does not include an active subunit of a G-protein or alternatively that GTP does not promote the dissociation of the receptor-G-protein complex. The presence of Na+ (100 mM) in the radioligand binding assay induced a biphasic decay curve for agonist binding and a flattening of the monoexponential decay curve for a partial agonist. In both cases the effect was explained by an irradiation-induced loss of the low affinity state of the opioid receptor produced by the addition of Na+. This suggests that an allosteric inhibitor that mediates the effect of sodium on the receptor is destroyed at low doses of irradiation, leaving receptors which are no longer regulated by sodium. The effect of Na+ on target size was slightly increased by the simultaneous addition of GTP but was not altered by pertussis toxin treatment. Thus, the sodium unit is distinct from G-proteins and may represent a new component of the opioid receptor complex. Assuming a simple bimolecular model of one Na+ unit/receptor, the size of this inhibitor can be measured as 168 kDa.
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PMID:Sodium modulates opioid receptors through a membrane component different from G-proteins. Demonstration by target size analysis. 283 94

Opioid receptors in intact NG 108-15 cells were irreversibly inactivated with increasing concentrations of the alkylating antagonist beta-chlornaltrexamine (CNA). The consequence of the reduction in density of opioid binding sites (quantified by saturation analysis of opioid binding in membranes) was studied at two steps of opioid receptor-mediated responses, (a) stimulation of high affinity GTPase and (b) inhibition of basal adenylate cyclase. Both agonist-mediated stimulation of GTPase and inhibition of adenylate cyclase activities were progressively reduced as the concentration of CNA in the pretreatment was increased. However, the loss of responsiveness for the two enzymes differed in two aspects. First, the diminution of GTPase responsiveness was in agreement with the loss of binding sites and took place at concentrations of CNA that were lower than those necessary to reduce responsiveness of adenylate cyclase. Second, the loss of responsiveness of GTPase occurred simply as reduction of maximal stimulation, whereas that of adenylate cyclase involved an initial reduction of apparent agonist affinity (10-fold) that was followed by a decrease in maximal effect. We next examined the loss of responsiveness of both GTPase and adenylate cyclase in membranes prepared from cells that had been exposed to increasing concentrations of pertussis toxin (PTX) to inactivate PTX-sensitive G proteins in vivo. Also in this case, the extent of reduction in responsiveness was more pronounced for GTPase than for adenylate cyclase, especially in membranes treated with high concentrations of PTX. However, the pattern of loss was identical for the two enzymes and involved a main reduction in maximal effect of the agonist that was followed only after a large degree of inactivation (greater than 60%) by a diminished apparent affinity for the agonist. Opioid receptor-mediated inhibition of cAMP accumulation in intact cells exhibits an IC50 for the agonist that is 30-10 times lower than that measured in membranes for stimulation of GTPase or inhibition of cyclase, respectively. Treatment of cells with either CNA (1 microM) or various concentrations of PTX altered the concentration-response curves for agonist-mediated inhibition of cAMP accumulation in a manner similar to that observed for adenylate cyclase in membranes, inasmuch as both maximal inhibition and apparent affinities for the agonist were decreased. However, this decrease in affinity (5-fold) was not sufficient to eliminate the discrepancy in agonist potency between membranes and intact cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Opioid receptors are coupled tightly to G proteins but loosely to adenylate cyclase in NG108-15 cell membranes. 284 42


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