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)

High-affinity binding sites for the D1 dopamine receptor antagonist [3H]SCH 23390 were identified in membranes from human putamen, frontal cortex and calf retina. In frontal cortex binding not only occurred to D1 but also to 5-HT2 receptors. In retina and putamen no binding to 5-HT2 receptors was detected. All further binding experiments in frontal cortex were carried out in the presence of 20 nM mianserin to prevent binding to 5-HT2 receptors. In the 3 tissues, antagonist competition curves were monophasic, whereas competition curves with the agonist dopamine revealed the presence of two binding sites, one having high affinity (RH) (32% in retina, 28% in putamen, and 15% in frontal cortex) and the other having low affinity (RL). In retina, the addition of 100 microM GTP caused a full conversion of RH into RL. In contrast, in frontal cortex, RH sites were not altered by 400 microM GTP or 100 microM 5'-guanylyl-imidodi-phosphate (Gpp(NH)p). In putamen, both guanine nucleotides provoked only a partial conversion of RH into RL. Dopamine (100 microM) produced a 220% and 56% increase in cAMP production in respectively retina and putamen homogenates, while no increase was observed in frontal cortex homogenate. These data may suggest that not all D1-receptors are coupled to the adenylate cyclase system.
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PMID:D1 dopamine receptors in human putamen, frontal cortex and calf retina: differences in guanine nucleotide regulation of agonist binding and adenylate cyclase stimulation. 289 59

The mesolimbocortical dopaminergic system innervates several brain regions including the frontal cortex. The aim of our work was both to identify and to pharmacologically characterize the dopamine receptors located in this brain area. We found that different selective agonists for D1 receptors were able to increase adenylate cyclase activity, and these effects were antagonized by haloperidol and SCH 23390. Moreover different agonists for D2 receptors inhibited the cyclic AMP generating system, and these effects were prevented by (-)-sulpiride. According to the paradigm that D1 receptors are linked with adenylate cyclase in a stimulatory way, while D2 receptors are linked with the same enzyme in an inhibitory way, our results indicate the presence of both D1 and D2 receptors in rat frontal cortex.
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PMID:Pharmacological characterization of D1 and D2 dopamine receptors in rat limbocortical areas. I. Frontal cortex. 289 17

The mesolimbocortical dopamine (DA) system innervates several brain regions including the hippocampus. The aim of the present study was both to identify and to pharmacologically characterize the DA receptors located in this brain area. The results show that different agonists for D1 DA receptors, such as DA itself, SKF82526 and (-)-apomorphine, were able to increase adenylate cyclase activity, and these effects were antagonized by haloperidol and SCH 23390. Moreover bromocriptine, lisuride and RU 24213, which are agonists for D2DA receptors, inhibited the cyclic AMP generating system and these effects were prevented by (-)-sulpiride. According to the paradigm that D1 DA receptors are linked with adenylate cyclase in a stimulatory way, while D2 DA receptors are linked with the same enzyme in an inhibitory way, our results indicate the presence of both D1 and D2 receptors in rat hippocampus. Localization studies show that both DA receptor subtypes are restricted to the dorsal part of the hippocampus.
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PMID:Pharmacological characterization of D1 and D2 dopamine receptors in rat limbocortical areas. II. Dorsal hippocampus. 289 18

The effects of dopamine (DA) and of two selective DA DA1 agonists (SKF 38393 and SKF 82526) on adenylate cyclase activity were studied with human kidney cortex membrane preparations. DA elicited a dose-related stimulation of adenylate cyclase activity with an EC50 of 60 microM. The selective DA DA1 antagonist SCH 23390 behaved as a competitive antagonist, shifting the dose-response curve to the right. The non-selective beta-adrenoceptor antagonist (-)-propranolol did not affect the EC50 of the dose-response curve to DA but attenuated the maximal stimulatory effect of DA at concentrations higher than 100 microM. (+)-Sulpiride inhibited DA-induced adenylate cyclase stimulation in a dose-dependent manner with an IC50 of 4.6 X 10(-8) M but (-)-sulpiride was without effect. Both SKF 38393 and SKF 82526 stimulated the adenylate cyclase activity of human kidney cortex; this effect was completely antagonized by SCH 23390. Our results, demonstrating the presence of DA-sensitive adenylate cyclase activity, strongly suggest the presence of a DA receptor of the DA1 subtype in human kidney cortex.
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PMID:Presence of dopamine-dependent adenylate cyclase activity in human renal cortex. 290 Jul 70

Forskolin markedly stimulates striatal adenylate cyclase activity in a concentration-dependent manner, and at 10(-4) M produces an approximate 40-fold increase in enzyme activity above basal levels. Dopamine (in the presence of 100 nM SCH 23390), bromocryptine and quinpirole (LY 171555) significantly inhibit both basal and forskolin-stimulated adenylate cyclase activity. There is a significant increase in the absolute but not in the percent inhibition of enzyme activity by dopaminergic agonists as a function of forskolin concentration. This inhibition is agonist-concentration dependent and antagonized by the D2 antagonist, spiperone. These results suggest that forskolin may be used as a tool for amplifying the abolute D2-receptor-mediated inhibition of adenylate cyclase in rat striatal homogenates.
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PMID:D2 dopamine receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in rat striatum. 293 59

On the basis of affinity differences for spiperone, two binding sites for [3H](+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene ([3H]ADTN) in the rat brain could be distinguished: "D3" with a low and "D4" with a high affinity for spiperone. Evidence is provided that D3 and D4 sites are related to high agonist affinity states of the D1 and D2 dopamine receptors, respectively. Various well-known selective D1 and D2 agonists and antagonists showed potencies at these sites in agreement with this hypothesis. A comparison of the Bmax values for [3H]ADTN binding to D3 and D4 sites with the numbers of D1 receptors (labelled by [3H]SCH 23390) and of D2 receptors (labelled by [3H]spiperone), both in the striatum and in the mesolimbic system, indicated that under the conditions used for 3H-agonist binding experiments, both populations of D1 and D2 receptors were converted to their high agonist affinity states to a considerable, although different extent. In fact, when competition experiments with [3H]spiperone were performed under the conditions otherwise used for [3H]ADTN binding experiments (instead of the conditions usually used for antagonist binding), substantial shifts of the displacement curves of 3,4-dihydroxyphenylethylamine (dopamine) and ADTN toward higher affinities were observed. A comparison of the effects of various agonists and antagonists in the [3H]ADTN binding experiments and in functional tests revealed a significant correlation between their potencies at D4 binding sites and at D2 receptors modulating the release of [3H]acetylcholine from striatal slices. However, in the situation of the D1/D3 pair, when the measurement of adenylate cyclase activity was taken as a functional test for D1 receptors, agonists were more active in the binding than in the functional test, whereas for many antagonists the opposite was found. The results are discussed with regard to the classification and functional aspects of brain dopamine receptors.
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PMID:Identification of dopamine "D3" and "D4" binding sites, labelled with [3H]2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, as high agonist affinity states of the D1 and D2 dopamine receptors, respectively. 293 68

We report here the functional relationship between the time-dependent recovery of [3H]SCH 23390-labeled D1 dopamine receptors and the D1 receptor-mediated stimulation of rat striatal adenylate cyclase activity following irreversible receptor modification by in vivo administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Initial decreases in receptor density (-93%) and receptor-mediated enzyme activity (-78%) were accomplished without concomitant changes in guanosine triphosphate or forskolin-stimulated enzyme activity. The percentage of maximal D1 receptor-mediated enzyme activity was significantly greater than that of D1 receptor density at all recovery times. Dopamine-stimulated enzyme activity returned to control values by day 4, although D1 receptor density remained significantly below control levels at this time. No differences in the EC50's for dopamine stimulation of enzyme activity were observed at any of the recovery times. These data demonstrate that the stoichiometric relationship between the recovering D1 dopamine receptors and D1 receptor-mediated enzyme activity is not one to one, providing evidence for the presence of 'spare' D1 dopamine receptors in rat striatum.
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PMID:Functional recovery of D1 dopamine receptor-mediated stimulation of rat striatal adenylate cyclase activity following irreversible receptor modification by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ): evidence for spare receptors. 294 28

It has been shown previously that typical neuroleptics have higher affinities for 3,4-dihydroxyphenylethylamine (dopamine) D1 receptors as labeled by (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-N-3-benzazepine- 7-ol ([3H]SCH 23390) than for inhibiting dopamine-stimulated adenylate cyclase. We now report that the atypical neuroleptics, clozapine and fluperlapine, exhibit characteristics opposite to typical neuroleptics, i.e., they have higher affinity for inhibiting dopamine-stimulated adenylate cyclase than [3H]SCH 23390 binding. A variety of compounds, i.e., clozapine, fluperlapine, and dopamine, were tested for their capacity to affect the rate constants of [3H]SCH 23390 binding. Treatment of striatal membranes with phospholipase A2 (PLA2) caused a rapid decrease in the Bmax value of the [3H]SCH 23390 binding with no effect on the KD value. The adenylate cyclase, both the unstimulated, the dopamine-, fluoride-, and forskolin-stimulated activity, was far less sensitive than [3H]SCH 23390 binding to PLA2. Treatment of striatal membranes with filipine and (NH4)2SO4 produced, as did PLA2 treatment, a rapid decline in [3H]SCH 23390 binding. However, opposite to PLA2 treatment, these agents stimulated the adenylate cyclase. In conclusion, a comparison of the pharmacological characteristics of [3H]SCH 23390 binding and dopamine-stimulated adenylate cyclase suggests the existence of two different D1 binding sites. The rate experiments exclude the possibility of allosterically coupled sites. Instead our results favor that the D1 receptor exists in different states/conformations, i.e., both adenylate cyclase-coupled and uncoupled, and further, that the atypical neuroleptics clozapine and fluperlapine may have adenylate cyclase-coupled dopamine D1 receptors as target.
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PMID:Evidence for different states of the dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor. 294 3

Unilateral lesions of the nigro-striatal dopamine (DA) pathway induced contralateral rotations to apomorphine, increased (3H)-spiroperidol binding and enhanced the sensitivity of striatal adenylate cyclase to DA stimulation. Prolonged L-dopa administration counteracted the increased density of (3H)-spiroperidol binding sites but further enhanced the hypersensitivity of adenylate cyclase to DA and decreased the inhibitory effect of opiates on this enzyme. The apomorphine-induced contralateral rotations were also strongly potentiated. On the contrary the binding of (3H)-SCH-23390 was affected neither by DA nerve degeneration nor by chronic L-dopa treatment. These results suggest that DA-D1 and DA-D2 receptors are differently affected by prolonged L-dopa treatment. The biochemical changes of DA-D1 receptors associated with adenylate cyclase seem to be correlated with the enhanced behavioural responses to apomorphine and could be a consequence of a decreased opiate inhibitory tone on the enzyme. The increased supersensitivity of the DA-D1 receptors may play a role in the clinical changes seen in parkinsonian patients following chronic use of L-dopa.
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PMID:Dopamine receptor changes in response to prolonged treatment with L-dopa. 294 13

The behaviour of rats was studied after combined treatment with the selective DA D-2 agonist quinpirole and three selective D-1 agonists (SK & F 38393, SK & F 75670 and Lu 24-040). The effects on behaviour were compared with those on receptor binding and adenylate cyclase (AC). While the D-1 agonists alone did not induce stereotyped behaviour, quinpirole induced dose-dependent hyperactivity (locomotion, sniffing, head movements and rearing), whereas licking/biting was absent or seen only occasionally. Combined treatment with quinpirole and a D-1 agonist was followed by dose-dependent licking and occasional biting behaviour. The D-1 agonists had similar efficacies, but SK & F 75670 and Lu 24-040 were more potent than SK & F 38393. The maximal effects of SK & F 38393 plus quinpirole were effectively blocked by either a D-1 antagonist (SCH 23390) or a D-2 antagonist (YM 09151-2) confirming the close relation between D-1 and D-2 receptor sites in the brain. Good correspondence was found between affinities to D-1 receptors [( 3H]SCH 23390 binding) in vitro and the EC50 values for stimulation of AC activity. However, the maximal effects on DA-sensitive AC activity were less for SK & F 75670 and Lu 24-040 than for SK & F 38393. Thus, the results indicate that efficacies in the adenylate cyclase assay are dissociated from those on behaviour. Furthermore, the data indicate that in normal rats D-1 receptors are functionally relevant since D-1 agonists facilitate the expression of oral stereotyped behaviour after combination with a D-2 agonist.
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PMID:Dopamine D-1 receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats. 294 91


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