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)

The norepinephrine-sensitive adenylate cyclase system in the rat brain was examined. Adrenergic blocking agents and the relative activity of structurally related catecholamines were employed to determine whether norepinephrine-stimulated accumulation of [3H]c-AMP in the hypothalamus occurred via alpha or beta adrenergic receptors. The results indicate that norepinephrine probably acts through a mixture of alpha and beta receptors in that both alpha and beta adrenergic blockers inhibited norepinephrine-induced accumulation of [3H]c-AMP. Morphine and levorphanol had no significant effect on adenylate cyclase or phosphodiesterase activities in hypothalamic slices or homogenates of several brain regions.
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PMID:Norepinephrine-sensitive adenylate cyclase in rat hypothalamus: effects of adrenergic blockers and narcotics. 2 29

The effects of consecutive oral administration of morphine on the cyclic AMP synthesizing system and cyclic AMP dependent protein kinase activity in the cerebral cortex of mice were examined. The administration of morphine (2--4 weeks) induced an increase of the cyclic AMP formation by activating adenylate cyclase, whereas responses of the cyclic AMP synthesizing system to biogenic amines (norepinephrine, dopamine and histamine) added in vitro was found to be significantly attenuated in these animals. Cyclic AMP dependent protein kinase activity in the cerebral cortex was also increased following a consecutive oral administration of morphine. These changes in the activities of adenylate cyclase and protein kinase were found mainly in crude mitochondrial and/or synaptosomal fractions. Morphine induced decrease in the response of the cyclic AMP synthesizing system to biogenic amines was rapidly reversed, and a significant increase of the cyclic AMP formation in the presence of added norepinephrine compared with that found in morphinized animals was observed following the administration of levallorphan, a narcotic antagonist. On the other hand, the changes in adenylate cyclase and cyclic AMP dependent protein kinase activities were not affected significantly by levallorphan administration. These results suggest that alterations in activities of cyclic AMP synthesizing system and of cyclic AMP dependent protein kinase may be involved in processes of the formation of morphine dependence. Possible involvement of abrupt increments in the sensitivity of "norepinephrine receptor-adenylate cyclase" system and a subsequent increase in cerebral cyclic AMP is also suggested as a cause of morphine withdrawal syndrome.
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PMID:Morphine-induced changes in cyclic AMP metabolism and protein kinase activity in the brain. 20 52

The effect of several concentrations of morphine on the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing): EC 4.6.1.1.] was measured in homogenates of caudate nuclei of mice. Morphine stimulated the enzyme at 500 micron and inhibited slightly at 5 micron. Morphine stimulation was blocked by naloxone. Depending on its dose, morphine also increased or decreased the stimulating effect of dopamine on the dopamine-sensitive adenylate cyclase activity of caudate homogenate. Like dopamine, morphine'e effect on the adenylate cyclase activity was increased or decreased, respectively, by pretreating the animals with poly(I).poly(C) or with chloramphenicol. Thus, both dopamine and morphine appear to act on the same receptor. This "new" receptor differs from the one described by Snyder et al. and others, who demonstrated only binding affinity and no enzymatic activity. These data indicate that certain functions of the opiates might be mediated through the dopamine-sensitive adenylate cyclase of the caudate nuclei, which are the dopamine receptors in the brain.
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PMID:Morphine sulfate stimulates the adenylate cyclase in mouse caudate nuclei. 20 8

Adenylate cyclase activity (AC) of homogenates of monkey amygdaloid nucleus was approximately doubled in the presence of dopamine (10 micrometer). Morphine, etorphine, and several enkephalin analogs (met-enkephalin, D-ala2-met-enkephalin, and D-met2, pro5-enkephalinamide) were capable of inhibiting the stimulation of AC produced by dopamine (90-100% with etorphine or D-ala2-met-enkephalin). Unlike morphine and etorphine, the peptides exhibited bell-shaped dose-response curves for this inhibition with maximal effects at approximately 1 X 10(-7) M, but negligible effects at 1 X 10(-5) M. Under the conditions studied, only etorphine inhibited basal AC. Naloxone antagonized the inhibitory effects of each of the opioids tested, and dextrorphan, an inactive L-(+)-opiate, failed to inhibit the dopamine response. Together these data indicate that the effects were mediated via the classically described stereospecific opiate receptor. The relative order of potency (etorphine greater than enkephalins greater than morphine) was similar to that previously reported for the binding affinities of these drugs in rat brain homogenates. The influence of narcotic agents on dopamine stimulated AC was eliminated by either freezing the amygdaloid tissue or preincubating the homogenate at 4 degrees C; the dopamine responses, however, could still be elicited. The narcotic receptor interaction with the adenylate cyclase thus appears to be distinct from and more labile than that of the dopamine receptor. Gpp(NH)p-stimulated AC was not inhibited by morphine. It is postulated that the inhibition involves interaction of opiate receptors with catalytic units of dopamine-stimulated AC, but not with other cyclase species which may provide the major component of Gpp(NH)p-stimulated activity in amygdala.
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PMID:Interaction of morphine, etorphine and enkephalins with dopamine-stimulated adenylate cyclase of monkey amygdala. 21 5

Analgesic doses of morphine and viminol R2 increase the turnover rate of dopamine (DA) in rat striatum but fail to increase the striatal concentration of adenosine 3',5'-monophosphate (cAMP) or the affinity of tyrosine hydroxylase (TH) for the pteridine cofactor. When morphine is added to striatal homogenates, it changes neither the basal activity of adenylate cyclase nor the enzyme activation by DA. Similarly to morphine, haloperidol enhances the turnover rate of striatal DA, but unlike morphine it increases the affinity of TH for the pteridine cofactor and blocks the in vitro activation of striatal adenylacte cyclase by DA. Morphine (52 mumol/kg i.p.), viminol R2 (7 mumol/kg i.p.) or haloperidol (2.6 mumol/kg i.p.) fails to increase the striatal cAMP contrations. However (+)-amphetamine (4.8 mumol/kg i.p.) increases DA turnover rate and the striatal cAMP content, but, in doses up to 12.8 mumol/kg i.p., it fails to change the affinity of TH for the pteridine cofactor. This study shows that although (+)-amphetamine, haloperidol and morphine increase the turnover rate of striatal DA each drug possesses a specific profile in its action on molecular mechanisms that control the function of striatal dopaminergic synapses.
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PMID:Molecular mechanisms in the actions of morphine and viminol (R2) on rat striatum. 23 24

Morphine inhibits adenylate cyclase (EC 4.6.1.1) activity of neuroblastoma times glioma hybrid cells. The inhibition is stereospecific and is reversed by the antagonist, naloxone. The relative affinities of narcotics for the opiate receptor agree well with their effectiveness as inhibitors of adenylate cyclase. Morphine-sensitive and -insensitive cell lines were found, and the degree of sensitivity was shown to be dependent upon the abundance of narcotic receptors. Thus, morphine receptors are functionally coupled to adenylate cyclase. A molecular mechanism for narcotic addiction and tolerance is proposed.
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PMID:Morphine receptors as regulators of adenylate cyclase activity. 105 41

In a previous paper, delta and kappa opiate receptors were shown to be co-localized on the same cell in enriched primary cultures of astroglia from neonatal rat cerebral cortex. Activation of the receptors inhibited adenylate cyclase. In this work, the presence of opiate receptors was investigated in astroglial primary cultures from neonatal rat striatum and brain stem. Cyclic adenosine 3',5'-monophosphate accumulation was quantified in the presence of different opioid receptor ligands after stimulation of the cyclic adenosine 3',5'-monophosphate system with forskolin. Morphine was used as a mu receptor agonist. [D-Ala2, D-Leu5]-enkephalin or [D-Pen2, D-Pen5]-enkephalin were used as delta receptor agonists and dynorphin 1-13 or U-50,488H were used as kappa receptor agonists. Specific antagonists for the respective receptors were used. After striatum or brain stem cultures had been incubated in 10(-9)-10(-5) M of each [D-Ala2, D-Leu5]-enkephalin, [D-Pen2, D-Pen5]-enkephalin and Dynorphin 1-13 or U-50,488H, dose related inhibitions of the 10(-5) M forskolin stimulated cyclic adenosine 3',5'-monophosphate accumulation were observed. The changes were reversed to the forskolin-induced control level in the presence of the respective antagonists. 10(-9)-10(-5) M morphine did not significantly change the forskolin-induced accumulation of cyclic adenosine 3',5'-monophosphate in the cultures studied. Furthermore, cultures from cerebral cortex, striatum or brain stem were incubated with isoproterenol alone or together with morphine or [D-Ala2, D-Leu5]-enkephalin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Delta and kappa opiate receptors in primary astroglial cultures. Part II: Receptor sets in cultures from various brain regions and interactions with beta-receptor activated cyclic AMP. 131 9

Previous studies have shown that chronic morphine increases levels of the G-protein subunits Gia and Goa, adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Gia and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of Gia seen in the NAc, increased levels of Gia and Goa in amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region.
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PMID:A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. 165 Nov 40

Morphine and ethanol drugs known to develop tolerance and dependence, induce changes in the adenylate cyclase system. Morphine inhibits the adenylate cyclase activity in NG108-15 cells and causes increases in adenylate cyclase synthesis and the down-regulation of opiate receptors in cells treated for several days. Chronic exposure of NG108-15 cells to ethanol also causes a decrease in the mRNA of the GTP-binding protein (Gs). These observations suggest the possibility that a group of genes is expressed in response to morphine or ethanol during the acquisition of tolerance and dependence. Recently, it has been reported that cAMP regulates a number of genes through a cAMP response element (CRE) in their promotor regions and that nuclear CRE-binding proteins bind specifically to the CRE to stimulate the transcription of cAMP-responsive genes. The gel shift assay with a single stranded oligo-DNA of CRE in a somatostatin promotor region was employed to examine the possibility of transcriptional regulation of cAMP-inducible genes by chronic morphine or ethanol treatment of NG108-15 cells. When the nuclear proteins from the cells treated with morphine or ethanol for several days were provided for the assay, the amounts of DNA-protein complex were decreased. The decreased complexes were recovered by 1-2 days after morphine withdrawal. The nuclear proteins were purified partially by a combination of chromatography on Q-Sepharose, Sephacryl S-300 and DNA affinity-Sepharose. Changes in CRE-binding proteins from the cells treated chronically with morphine or ethanol suggest that these drugs can modulate the expression of cAMP-inducible genes through which tolerance and dependence may develop.
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PMID:[Molecular mechanism of drug tolerance and dependence]. 166 Apr 43

Morphine, a potent analgesic drug as well as the active metabolite derived from heroin, has been reported to affect a variety of immune functions. In vivo administration of high doses of morphine to animals has been shown to inhibit natural killer (NK) cell activity in the rat (Shavit et al., 1984) and splenic T cell mitogenic response in the mouse (Bryant et al., 1988). We report here on the effect of morphine sulfate (MS) (0.2-1.6 mM) on Concanavalin-A (Con-A) stimulated lymphokine production by mouse splenocytes in vitro. Twenty-four hour incubation of mouse splenocytes with MS, removal of the drug and activation with Con-A resulted in a significant (linear regression, P less than 0.001) dose-related inhibition of lymphokine production (IC50 = 0.8 mM) as measured by bioassay for interleukin-2 (IL-2)/interleukin-4 (IL-4). The inhibitory effect of MS on lymphokine production was not blocked by opiate antagonists nor was the inhibitory effect mimicked by equivalent concentrations of mu, delta or epsilon receptor-specific opiate agonists. Exposure to the concentrations of MS used did not reduce viability of mouse splenocytes as determined by Trypan Blue exclusion. Morphine did not inhibit protein synthesis or adenylate cyclase activity in a T cell clone under identical conditions, indicating that MS, in this concentration range, does not simply interfere with all cell functions in a nonspecific manner. These results suggest that (1) morphine directly inhibits splenocyte function, (2) the inhibitory effect is not mediated through classical opiate receptors, and (3) the inhibitory effect is not due to toxicity.
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PMID:Effect of high doses of morphine on Con-A induced lymphokine production in vitro. 166 96


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