Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using rotorod performance as the test response, possible modulation and co-modulation of ethanol-induced motor incoordination by the cerebellar kappa-opioid and adenosine A1 receptors was studied. A dose-related accentuation of ethanol-induced motor incoordination was observed after direct cerebellar microinfusion of three kappa-opioid receptor agonists: U-50488, U-62066, and bremazocine. On the contrary, significant and dose-related attenuation of ethanol's motor impairment was produced by intracerebellar nor-binaltorphimine, a kappa-opioid receptor antagonist. Furthermore, the accentuation by kappa-agonists was virtually abolished by kappa-antagonist nor-binaltorphimine. Therefore, the accentuation and attenuation by kappa-opioid receptor agonists/antagonist, respectively, was through specific kappa-opioid receptors. Pretreatment with the intracerebellar adenosine A1-selective agonist, N6-cyclohexyladenosine, further enhanced the ethanol-induced motor incoordination and its accentuation by intracerebellar kappa-opioid receptor agonists. Ethanol-induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX-sensitive G protein in the expression of motor incoordinating effect of ethanol. Additionally, the intracerebellar PTX also markedly attenuated the accentuation by kappa-opioid agonists of ethanol-induced motor impairment, suggesting participation of PTX-sensitive GTP-binding G protein (Gi, Go) in the kappa-opioid modulation of ethanol's motor impairment. It also confirms that kappa-opioid receptors are linked to PTX-sensitive G protein. The functional similarity between kappa-opioid and adenosine A1 receptors in increasing ethanol's motor incoordination, together with their anatomical co-localization primarily on the axons and axonal terminals of the cerebellar granule cells, suggests a possible common catalytic unit of adenylate cyclase as the basis of modulation of ethanol-induced motor incoordination by both receptor mechanisms.
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PMID:Involvement of kappa-opioids in the mouse cerebellar adenosinergic modulation of ethanol-induced motor incoordination. 958 52

To investigate cellular adaptation responses induced by chronic agonist treatment of the mu-opioid receptor, Chinese hamster ovary (CHO) cells were stably transfected with the rat mu-opioid receptor cDNA. Chronic treatment with agonists selective for the mu-opioid receptor, [D-Ala2, N-MePhe4, Gy-ol5]enkephalin (DAMGO), morphine and fentanyl, time- and dose-dependently induced down-regulation of the mu-opioid receptor. The down-regulation was not significantly affected by pretreatment with pertussis toxin, but was completely blocked by treatment with hypertonic sucrose, suggesting that receptor internalization mediated by clathrin-coated vesicles is an essential step in the mu-opioid receptor down-regulation. On the other hand, forskolin-stimulated cyclic AMP formation was increased by chronic DAMGO treatment, which was inhibited by pertussis toxin pretreatment. These results indicate that two adaptation responses induced by chronic agonist treatment of the mu-opioid receptor-expressing CHO cells, down-regulation of the mu-opioid receptor and supersensitization of adenylate cyclase, are mediated by distinct mechanisms.
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PMID:Adaptations to chronic agonist exposure of mu-opioid receptor-expressing Chinese hamster ovary cells. 960 Jun 41

In the present study, the functional significance of the intracellular C-terminal loop of the mu-opioid receptor in activating Gi proteins was determined by constructing a C-terminal deletion mutant mu(C delta 45) receptor, which lacks the carboxyl 45 amino acids. When the truncated mu(C delta 45) receptor was stably expressed in human embryonic kidney (HEK) 293 cells, the efficacy and the potency of [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO), a specific mu-opioid receptor agonist, to inhibit forskolin-stimulated adenylate cyclase activity were not significantly affected. Similar to other G-coupled receptors, the third cytoplasmic loop of the mu-opioid receptor contains conserved basic residues (R276/R277/R280) at the C-terminal segment. Mutating these basic residues to neutral amino acids (L276/M277/L280) greatly impaired the ability of DAMGO to inhibit forskolin-stimulated cyclic AMP formation. Replacing R276/R277 with L276/M277 did not affect the efficacy and potency by which DAMGO inhibits the adenylate cyclase activity. In HEK 293 cells stably expressing mutant (R280L) mu-opioid receptors, the ability of DAMGO to inhibit forskolin-stimulated cyclic AMP production was greatly reduced. These results suggest that the intracellular carboxyl tail of the mu-opioid receptor does not play a significant role in activating Gi proteins and that the arginine residue (R280) at the distal third cytoplasmic loop is required for Gi activation by the mu-opioid receptor.
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PMID:A conserved arginine in the distal third intracellular loop of the mu-opioid receptor is required for G protein activation. 1003 4

Although naturally occurring antibodies have been associated with numerous biological activities, their functional relevance is still a matter of debate. The presence of natural autoantibodies towards immune-related molecules such as cytokines and antibodies suggests a physiological immunomodulatory role. The neuroendocrine opioid system participates in the immune homeostasis. We report here the presence of antibodies with an agonist-like activity towards the human mu-type opioid receptor within a normal human IgG pool. Starting from an IgG pool, autoantibodies were affinity purified using Chinese hamster ovary cells expressing the human mu-opioid receptor. Their specificity was assessed by cytofluorometry and pharmacological analyses. The potency of these antibodies to recognize the mu-opioid receptor was similar to mu-opioid selective agonists. Furthermore, the functional opioid-like activity of the anti-opioid receptor IgG was demonstrated by their ability to inhibit adenylate cyclase activity by a Gi/o-protein-mediated mechanism as indicated by abrogation of the effect by either opioid antagonist or pertussis toxin. Five IgG pools, each from four unrelated healthy blood donors, and single IgG preparations from six other donors were prepared. Antibodies directed against the mu-opioid receptor were found in all IgG samples.
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PMID:Isolation and characterization of natural human IgG with a morphine-like activity. 1009 4

The kappa-opioid receptor exerts a negative modulatory action on the beta-adrenoceptor and the action is blunted in adult spontaneously hypertensive rats (SHR). In order to determine whether the blunted negative modulation of the beta-adrenoceptor by the kappa-opioid receptor contributes to the development of hypertension, the electrically induced intracellular calcium ([Ca2+]i) transient was measured in single ventricular myocytes of SHR at 4, 6, 8 and 13-week-old and the age-matched Wistar Kyoto (WKY) rats. The electrically induced [Ca2+]i transients were augmented by norepinephrine (NE), a beta-adrenoceptor agonist, over four-fold in WKY rats of all ages studied and in SHR of 4 and 6 weeks of age. The enhancing effect of NE in 8- and 13-week-old SHR was, however, only approximately three-fold, significantly lower than the corresponding values in age-matched WKY rats. Similarly, the electrically induced [Ca2+]i transients were also augmented by forskolin, an activator of adenylate cyclase, by approximately two-fold in WKY rats of all ages and SHR aged 4 and 6 weeks. In SHR aged 8 and 13 weeks, the effect of forskolin was only 1.5-fold, significantly lower than the two-fold increase in the corresponding WKY rats. The enhancing effects of NE and forskolin were attenuated by U50,488H, a selective kappa-opioid agonist, by approximately 50 and 25%, respectively, in both types of rats of all ages studied, with the exception of 13-week-old rats. In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY. The fact that attenuation of U50,488H on the enhancing effects of NE and forskolin only occurs in 13-week-old SHR when hypertension has been fully developed indicates that the attenuated inhibitory modulation of kappa-opioid receptor stimulation does not contribute to the initiation of hypertension. Interestingly, the enhancing effects of NE and forskolin on the electrically induced [Ca2+]i transient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation of kappa-receptor stimulation on the beta-adrenergic receptor is not due to the signal transduction pathway activated by beta-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation of beta-adrenergic and kappa-opioid receptors and adenylate cyclase are not secondary to hypertension.
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PMID:Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats. 1019 90

We have previously demonstrated that randomly selected healthy individuals express anti-human mu-opioid receptor antibodies which behave as agonist in vitro. In this study, we show that the activity of these antibodies was not affected by the deletion of the amino-terminal region of the receptor. Using agarose-bound peptide columns, we affinity-purified IgG specifically directed toward each extracellular loop. Whatever its specificity, each anti-human mu-opioid receptor (hMOR) extracellular loop peptide IgG preparation was unable, when examined individually, to reduce adenylate cyclase activity. Activation of the hMOR was, however, achieved by the simultaneous binding of IgG to the first and third extracellular loops of the receptor. Our results suggest that the simultaneous binding of IgG antibodies to these two loops mimics morphine-induced receptor activation by triggering a coordinated shift of the third and sixth transmembrane helices.
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PMID:Morphine-like activity of natural human IgG autoantibodies is because of binding to the first and third extracellular loops of the mu-opioid receptor. 1040 Jun 17

To investigate the cellular and molecular basis for using methadone in substitution therapy for morphine addiction, the difference between methadone and morphine in causing desensitization of delta-opioid receptors was examined, and the effects of methadone pretreatment on opiate-induced inhibition of forskolin-stimulated cAMP accumulation was studied. Methadone substantially attenuated the ability of [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and methadone to inhibit forskolin-stimulated cAMP accumulation. Methadone was able to block the morphine-induced compensatory increase in intracellular cAMP levels and naloxone-precipitated cAMP overshoot after chronic exposure to morphine. The protein kinase inhibitor (1-5-isoquinolinesulfony)-2-methylpiperazine) (H7) could significantly block the chronic methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine was able to block the acute methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. In contrast, morphine did not cause a substantial desensitization of the delta-opioid receptor. These results indicate that methadone is different from morphine in its regulation of the delta-opioid receptor. In addition, these results also indicate that the mechanisms of delta-opioid receptor desensitization induced by acute and chronic methadone treatment are different.
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PMID:The difference between methadone and morphine in regulation of delta-opioid receptors underlies the antagonistic effect of methadone on morphine-mediated cellular actions. 1041 44

Chronic exposure of neuroblastoma x glioma (NG108-15) hybrid cells and rat mu-receptor-transfected Chinese hamster ovary (CHO) cells to 10 microM morphine resulted in a compensatory and antagonist-precipitated increase in cAMP accumulation. However, incubation of these cells with 10 microM methadone during chronic exposure to morphine substantially prevented the actions of morphine. Chronic methadone treatment caused a pronounced reduction in agonist-stimulated binding of [35S]GTPgammaS to G proteins, but it did not produce significant down-regulation of delta-opioid receptors, whereas chronic morphine treatment failed to induce either uncoupling of delta-opioid receptors from G proteins or down-regulation of delta-opioid receptors. In contrast to chronic treatment with morphine alone, treatment of cells with morphine and methadone simultaneously resulted in a significant decrease in agonist-stimulated binding of [35S]GTPgammaS to G proteins. The action of methadone-mediated uncoupling of the receptor from the G protein was blocked by the nonselective protein kinase inhibitor [1-(5-isoqinolinesulfony)-2-methylpiprazine](H7), but not by the specific protein kinase C inhibitor, chelerythrine. The data demonstrate that methadone desensitizes the delta-opioid receptor by uncoupling the receptor from the G protein. In this way, methadone antagonizes the morphine-mediated adaptive sensitization and overshoot of adenylate cyclase. The functional desensitization of opioid receptors by methadone may explain why methadone is effective in the treatment of morphine dependence.
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PMID:Methadone-induced desensitization of the delta-opioid receptor is mediated by uncoupling of receptor from G protein. 1042 72

Differences in the specificity of coupling of delta-opioid receptor with G-protein have been reported in the literature. We have observed a differential desensitization of delta-opioid receptors, endogenously expressed in the neuroblastoma cell line SK-N-BE, induced by peptide and alkaloid agonists. By combining photoaffinity labelling of receptor-activated G-proteins with [alpha-(32)P]azidoanilide-GTP and an anti-sense oligodeoxynucleotide strategy, we examined whether the chemical nature of opioid agonists, alkaloid or peptide, has a critical role in determining a G(i)alpha/G(o)alpha-protein-selective activation by the human delta-opioid receptors. Etorphine, a non-selective alkaloid agonist, was shown to stimulate the incorporation of [alpha-(32)P]azidoanilide-GTP into G(i)alpha1, G(i)alpha2, G(i)alpha3 and pertussis-toxin-insensitive Galpha subunits. In contrast, [d-Pen(2),d-Pen(5)]enkephalin (DPDPE; Pen is penicillamine) and Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH(2) (deltorphin I), selective peptide agonists, mainly activated G(i)alpha2 and G(o)alpha2 subunits. The 'knock-down' of G(o)alpha2 subunits by anti-sense oligodeoxynucleotides selectively decreased the inhibition of adenylate cyclase induced by DPDPE and deltorphin I, whereas anti-sense oligodeoxynucleotides directed against G(i)alpha2 subunits only decreased the potency of etorphine in inhibiting cAMP accumulation. These results suggest that the nature of the agonist, peptide or alkaloid is critical in determining the interaction between human delta-opioid receptors and Galpha subunits.
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PMID:Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE. 1043 2

During myocardial ischaemia the beta-adrenoceptor is activated, which contributes, at least partly, to cardiac arrhythmias via inducing [Ca2+]i oscillations. Since beta-adrenoceptor is negatively modulated by the kappa-opioid receptor in the heart, the present study attempted to determine if kappa-opioid receptor stimulation modulates the arrhythmogenic action of beta-adrenoceptor stimulation and to delineate the underlying mechanism. The effect of U50,488H, a selective kappa-opioid agonist, on arrhythmias in the isolated perfused rat heart subjected to low flow and 10(-6)mol/l norepinephrine (NE) were determined. Low flow induced arrhythmias, which were potentiated by NE, but not by 10(-6)mol/l U50,488H. The arrhythmia-potentiating effect of NE was antagonized by 10(-6)mol/l propranolol, a beta-adrenoceptor antagonist. U50,488H at 10(-6)mol/l also abolished the potentiation in arrhythmias by NE without affecting the arrhythmias induced by low flow. The anti-arrhythmic action of the kappa-opioid receptor agonist was abolished by 10(-6)mol/l nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by 10(-7)mol/l calphostin C, an inhibitor of protein kinase C. Similarly, kappa-opioid receptor stimulation with U50,488H also abolished the NE-induced [Ca2+]i oscillations which are believed to cause cardiac arrhythmias, in ventricular myocytes. To determine whether the inhibitory actions of U50,488H against the effects of beta-adrenoceptor stimulation was via a cAMP-dependent or a cAMP-independent pathway, we determined the effects of U50,488H on NE-enhanced cAMP production and [Ca2+]i oscillations induced by either forskolin, an activator of adenylate cyclase, or Bay K-8644, a selective L-type Ca2+ channel agonist, in the ventricular myocytes. We found that U50,488H abolished the effect of forskolin, but did not alter the effect of Bay K-8644, on [Ca2+]i oscillations in the ventricular myocyte. In addition, U50, 488H also attenuated significantly the NE-induced elevation in cAMP in the heart. The observations suggest that kappa-opioid receptor stimulation abolishes the effect of beta-adrenoceptor stimulation on arrhythmias and [Ca2+]i oscillation via a cAMP-dependent pathway. The finding may be useful for the prevention and treatment of ischaemic heart diseases.
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PMID:Anti-arrhythmic effect of kappa-opioid receptor stimulation in the perfused rat heart: involvement of a cAMP-dependent pathway. 1052 19


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