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

---

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

3H-noradrenaline release from rat neocortical slices induced by 15 mM K+ was concentration-dependently inhibited by morphine, [D-Ala2-D-Leu5] enkephalin (DADLE) and the calcium entry blocker Cd2+. Blockade of presynaptic alpha 2-adrenoceptors with phentolamine, almost doubling K+-induced 3H-noradrenaline release, slightly enhanced the relative inhibitory effects of morphine and DADLE, whereas that of Cd2+ remained unaffected. In contrast, activation of presynaptic alpha 2-adrenoceptors with clonidine (1 microM) or TL-99 (1 microM), inhibiting release by about 50%, completely abolished the inhibitory effects of morphine and DADLE without affecting that of Cd2+. When in the presence of 1 microM clonidine adenylate cyclase was activated with forskolin (10 microM), which restored release to the drug-free control level, the opioids still did not display their inhibitory effects. Therefore, mu-opioid receptor efficacy appears to be dependent on the degree of activation of alpha 2-adrenoceptors in central noradrenergic nerve terminals, probably through a local receptor interaction within the nerve terminal membrane.
...
PMID:Activation of presynaptic alpha 2-adrenoceptors attenuates the inhibitory effect of mu-opioid receptor agonists on noradrenaline release from brain slices. 302 59

The activity of adenylate cyclase in striatal membrane-enriched fractions (25,000 g) was inhibited by morphine, beta-endorphin, [D-Ala2-D-Leu5] enkephalin (DADLenk), fentanyl and bremazocine. Whereas guanosine triphosphate (GTP) appeared essential for the expression of this effect, sodium chloride seemed to enhance the degree of inhibition. Dopamine stimulation and sodium fluoride activation of the enzyme was also suppressed by morphine, beta-endorphin and DADLenk. beta-Endorphin and DADLenk inhibited adenylate cyclase activity in vasa deferentia membrane-enriched fractions (25,000 g); both opioids required GTP and NaCl and were inhibited by a delta-opioid receptor antagonist and by naloxone. Morphine, bremazocine and tifluadom did not significantly alter the activity of the vas deferens enzyme. Basal cyclic AMP values of striatal slices were not significantly altered by morphine, beta-endorphin or DADLenk. However, dopamine-induced elevation of cyclic AMP was reduced by morphine and this effect of the opiate was suppressed by naloxone. Only beta-endorphin lowered the basal cyclic AMP values in the vas deferens. The physiological relevance of adenylate cyclase coupling to opioid receptor subtypes is considered.
...
PMID:Opioid inhibition of adenylate cyclase in the striatum and vas deferens of the rat. 302 42

The time course of opioid receptor binding disappearance and loss of responsiveness of the opioid-controlled GTPase and adenylate cyclase were compared in membranes derived from NG108-15 cells pretreated with the opioid peptide agonist [D-Ala2,D-Leu5]enkephalin (DADLE). Upon pretreatment with DADLE, a rapid desensitization of the opioid-stimulated GTPase occurred with a time course distinguishable as two exponential components having respective half-lives of 5-9 and 60-80 min. Opioid receptor binding activity, as assessed using [3H]diprenorphine, also decayed as two exponential components whose half-lives were similar to those for GTPase desensitization (7 and 120 min). However, when [3H]diprenorphine binding was measured in the presence of sodium and GTP, only the second, slow component was apparent. In contrast, desensitization of the opioid-controlled adenylate cyclase occurred as only one exponential decaying process, displaying a half-life of 57 min. Whereas the loss of responsiveness of GTPase to DADLE was entirely accounted for by a reduction in the maximal stimulation produced acutely by DADLE, desensitization of adenylate cyclase was characterized by both a decrease in maximal inhibition and a shift to the right of the EC50 of the agonist in inhibiting acutely the enzyme. In addition, after 1 hr of pretreatment with DADLE, the opioid-stimulated GTPase was desensitized by 65%, whereas 80% of maximal inhibition of adenylate cyclase could still be achieved. We suggest that: the rapid loss of responsiveness of the opioid-GTPase system results from an uncoupling between the receptor and the nucleotide-binding regulatory protein (N); the fast decaying GTPase activity appears to be not directly related to the opioid-mediated inhibition of adenylate cyclase; and the slow decaying GTPase activity, as well as the desensitization of the opioid-adenylate cyclase, is most likely accounted for by down-regulation of the opioid receptor. These findings may indicate that part of the opioid-stimulated GTPase in the membrane is not involved in inhibition of the cyclase and could reflect the activity of a regulatory protein which couples opioid receptors to another membrane effector. Alternatively, they might be interpreted on the basis of a model which involves a tight coupling between receptor activation and N protein and a large amplification mechanism between N protein and adenylate cyclase.
...
PMID:GTPase and adenylate cyclase desensitize at different rates in NG108-15 cells. 302 28

D-1 dopamine receptor-stimulated cyclic AMP efflux from rat neostriatal slices (induced by 30 microM dopamine + 10 microM (-)sulpiride) was concentration-dependently reduced by morphine, [D-Ala-D-Leu]-enkephalin (DADLE), [D-Pen-D-Pen]enkephalin (DPDPE) and bremazocine. Naloxone (0.1 microM) selectively antagonized the inhibitory effect of (a submaximally effective concentration of) morphine, whereas ICI 174864 (0.75 microM) completely blocked the inhibitory effects of DADLE, DPDPE and bremazocine without affecting that of morphine, indicating a role of mu- as well as delta-opioid receptors. Upon simultaneous activation of D-1 dopamine receptors and delta-opioid receptors the (mu-receptor-mediated) inhibitory effect of morphine was abolished, while it was not changed following simultaneous activation of D-1 and (inhibitory) D-2 dopamine receptors. Cyclic AMP efflux induced by isoprenaline or adenosine was not affected by the opioids and that induced by vasoactive intestinal peptide (VIP) was inhibited by morphine and DADLE only. In the latter case naloxone, but not ICI 174864, antagonized the inhibitory effects. These data show that D-1 dopamine receptor-stimulated adenylate cyclase activity in rat neostriatum, but not that stimulated through other receptors, is inhibited by two pharmacologically distinct opioid receptor subtypes. It is speculated that these mu- and delta-opioid receptors share a common inhibitory guanine nucleotide binding protein and may represent closely associated recognition sites of a functional opioid receptor complex.
...
PMID:Inhibition of dopamine-sensitive adenylate cyclase by opioids: possible involvement of physically associated mu- and delta-opioid receptors. 303 83

Using the mouse delta-opioid receptor cDNA as a probe, we have isolated genomic clones encoding the human mu- and kappa-opioid receptor genes. Their organization appears similar to that of the human delta receptor gene, with exon-intron boundaries located after putative transmembrane domains 1 and 4. The kappa gene was mapped at position q11-12 in human chromosome 8. A full-length cDNA encoding the human kappa-opioid receptor has been isolated. The cloned receptor expressed in COS cells presents a typical kappa 1 pharmacological profile and is negatively coupled to adenylate cyclase. The expression of kappa-opioid receptor mRNA in human brain, as estimated by reverse transcription-polymerase chain reaction, is consistent with the involvement of kappa-opioid receptors in pain perception, neuroendocrine physiology, affective behavior, and cognition. In situ hybridization studies performed on human fetal spinal cord demonstrate the presence of the transcript specifically in lamina II of the dorsal horn. Some divergences in structural, pharmacological, and anatomical properties are noted between the cloned human and rodent receptors.
...
PMID:kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. 762 59

Continuous elevation of intracellular cyclic AMP (cAMP) by culturing neuroblastoma x glioma NG108-15 hybrid cells in the presence of forskolin and isobutylmethylxanthine (IBMX) in a chemically defined medium resulted in differentiation of the hybrid cells, as indicated by extension of neurite-like structures and induction of a subclass of G-protein, Go, as monitored by Western analysis. This cellular differentiation also resulted in an initial 25 to 30% increase in [3H]diprenorphine binding 3 hr after forskolin and IBMX treatment, followed by a decrease in opioid receptor density to the maximal level of 35% of control 4 days later. However, the potencies and maximal inhibitory levels of various opioid agonists to inhibit adenylate cyclase activity was not altered during differentiation. When the differentiated hybrid cells were treated with DADLE chronically, an apparent decrease in the ability of the agonist to desensitize and to down-regulate the delta-opioid receptor was observed. It is unlikely that this observed attenuation was due to activation of cAMP-dependent protein kinase A, because (1) attenuation of DADLE desensitization was time-dependent, reaching maximal effects 48 hr after the initiation of treatment; and (2) pretreatment of NG108-15 cells with forskolin and IBMX resulted in attenuation of forskolin's ability to stimulate adenylate cyclase activity and parallel decrease in the ability of forskolin to activate the cAMP-dependent protein kinases in these cells was also observed. Thus, it is unlikely that the activation of protein kinase A by forskolin and IBMX is the cause for the attenuation of DADLE-induced delta-opioid receptor desensitization in differentiated NG108-15 cells.
...
PMID:Effect of forskolin and isobutylmethylxanthine on delta-opioid receptor activity in neuroblastoma x glioma NG108-15 cells. 768 Jul 18

Repeated, once daily morphine treatment (14 days) as well as chronic morphine administration (6 days) caused a rebound reduction in the electrically evoked release of [3H]dopamine from superfused rat striatal slices 1 day after the last subcutaneous injection. Interestingly, whereas [3H]dopamine release remained significantly reduced for at least 3 weeks following morphine withdrawal in chronically treated (tolerant/dependent) rats, neurotransmitter release from dopaminergic nerve terminals gradually increased above control values following cessation of repeated morphine administration. Postsynaptically, dopamine D1 receptor-stimulated adenylate cyclase appeared to be sensitized 1-3 days but was unchanged 3 weeks after chronic morphine treatment. In contrast, such an enhanced postsynaptic dopamine D1 receptor efficacy did not occur 1-3 days following repeated morphine administration, but appeared to develop slowly resulting in a profound increase of dopamine-sensitive adenylate cyclase 3 weeks after the last injection. The inhibitory effect of dynorphin A-(1-13) on [3H]dopamine release, as well as that of [Met5]enkephalin on dopamine D1 receptor-stimulated adenylate cyclase appeared to be unchanged subsequent to repeated or chronic morphine treatment. These data indicate that, long after cessation of drug treatment, chronic morphine treatment causes a reduction whereas repeated morphine administration gradually induces an enhancement of opioid receptor-regulated dopaminergic neurotransmission due to local adaptive changes within the rat striatum. Such distinct long-lasting alterations of dopaminergic neurotransmission induced by different temporal patterns of morphine administration in projection areas of mesencephalic dopaminergic neurons may be related to the enduring effects of drug abuse such as behavioural sensitization and drug craving.
...
PMID:Repeated and chronic morphine administration causes differential long-lasting changes in dopaminergic neurotransmission in rat striatum without changing its delta- and kappa-opioid receptor regulation. 790 81

This study was designed to evaluate the effects of a chronic treatment with the classical neuroleptic drug haloperidol on the preproenkephalin (ppEnk) mRNA synthesis and its consequences for opioid and dopamine (DA) receptor-regulated adenylate cyclase in the developing and adult rat striatum. Prenatal exposure to haloperidol (2 mg/kg, 14 days) caused a 40% reduction of striatal ppEnk mRNA levels, but had no consequences for DA-stimulated or Met-enkephalin-inhibited adenylate cyclase activity in striatal slices from embryonic day 21 (E21) foetal brain. Postnatal treatment of rat pups from day 10 (P10) until P23 and adult rats resulted in significant increases of mRNA levels of 8 and 41%, respectively, a clear reduction of D1 DA receptor-stimulated cAMP production and a profound desensitization of delta-opioid receptors inhibitory coupled to adenylate cyclase. Since striatal D2 receptor-mediated inhibition of adenylate cyclase activity, in contrast to its activation through D1 receptors, is not present in the prenatal period, this study indicates that the tonic inhibitory effect of DA on striatal ppEnk mRNA synthesis is dependent on the presence of adenylate cyclase-coupled D2 receptors which gradually develops postnatally and further supports the idea that striatal D1 and D2 DA receptors have bidirectional effects on enkephalin synthesis in this brain area. The adaptive changes in D1 DA and delta receptor-regulated adenylate cyclase activity are discussed in relation to the well-known increase in the locomotor and reinforcing effects of mu-opioid receptor agonists upon chronic neuroleptic treatment.
...
PMID:Adaptive changes in rat striatal preproenkephalin expression and dopamine-opioid interactions upon chronic haloperidol treatment during different developmental stages. 791 3

In this work, we have characterized the opioid receptor expressed by the human neuroblastoma cell line SK-N-BE and compared its hydrodynamic behaviour with those of well known opioid receptors: mu-opioid receptor of rabbit cerebellum and delta-opioid receptor of the hybrid cell line NG 108-15. Human neuroblastoma cell line SK-N-BE expresses a substantial amount of opioid receptors (200-300 fmoles/mg of protein). Pharmacological characterization suggests an heterogenous population of receptors and the presence of two delta subtypes which are, at least partially, negatively coupled with adenylate cyclase via a Gi protein. These receptors exist under two different molecular forms and, in this respect, strikingly contrast with the archetypic delta receptors of NG 108-15 hybrid cell line which show only a high molecular weight form and appear more tightly coupled with the G protein. Hydrodynamic behaviour of SK-N-BE opioid receptors is reminiscent of the profile observed with the rabbit cerebellum mu-opioid receptor. This observation is consistent with the presence of two delta-opioid receptors subtypes, one of which exhibiting properties close to those of mu opioid receptors. Taken overall, our results suggest that different types and subtypes of opioid receptors, even if they are coupled to the same inhibitory G protein, are more or less tightly coupled with their transduction proteins and that closely related opioid receptors can form allosterically interacting complexes.
...
PMID:Different subtypes of opioid receptors have different affinities for G-proteins. 792 Jan 83

To investigate roles of second extracellular loop sequences in peptide and nonpeptide ligand recognition by human opiate receptors, we have constructed a chimeric receptor in which this domain of the human mu opiate receptor has been replaced with that of the human kappa opiate receptor. The chimeric opiate receptor displays dramatically increased affinity for dynorphin peptides. Affinities for dynorphin A-(1-17), dynorphin A-(1-13), and alpha-neoendorphin increase by up to 250-fold when compared with the wild-type human mu opiate receptor. The chimera maintains recognition of the mu-selective ligands morphine and [D-Ala2,MePhe4,Gly-ol5]enkephalin and displays no significant changes in affinity for the kappa-selective small molecule ligand U50,488. The chimeric opiate receptor displays evidence for effective G-protein coupling; 100 nM dynorphin A-(1-17) is as effective as 100 nM morphine at inhibiting forskolin-stimulated adenyl cyclase activity through actions at the chimeric receptor. These data suggest that the putative second extracellular loop contributes substantially to the kappa receptor's selectivity in dynorphin ligand recognition.
...
PMID:Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras. 792 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---