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)

1. Adenylate cyclase activity was assayed in the optic lobe of Octopus vulgaris. 2. Both octopamine and dopamine stimulate the octopus adenylate cyclase, apparently by competing with the same receptor site. 3. (+/-)-2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene-HBr (6,7-ADTN) and a number of phenylethanolamine derivatives stimulate the octopus adenylate cyclase activity. 4. The dopamine D-1 antagonists R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH-23390) and (+/-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine-HCl (SKF-83566) are unable to antagonize the effects of dopamine and octopamine, and similarly ineffective is the agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine-7,8-diol-HCl (SKF-38393). 5. No detectable binding of labelled SCH-23390 occurs on membrane preparations from octopus optic lobe.
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PMID:A dopamine- and octopamine-sensitive adenylate cyclase in the nervous system of Octopus vulgaris. 178 63

Apomorphine, used in small doses (20-50 micrograms/kg), induced an increase in the activity of an endogenous inhibitor of cAMP dependent protein kinases (Walsh inhibitor, type I inhibitor) in nucleus accumbens of the rat. The action of apomorphine was blocked by sulpiride and aminophylline and enhanced by SCH-23390. Pretreatment with 6-OH-dopamine resulted in a shift of the dose-response curve for apomorphine to the left, suggesting supersensitivity of D2 receptors. Moreover, stimulation of D2 receptors induced a decrease in phosphorylation of DARPP-32, a specific protein, located in neurones containing D1 receptors. Large doses of apomorphine (over 0.5 mg/kg) provoked a decrease in type I inhibitor activity, blocked by SCH-23390 and enhanced by sulpiride and aminophylline. Moreover, SCH-23390 blocked a decrease in type I inhibitor activity induced by large doses of sulpiride and sulpiride blocked an increase in type I inhibitor activity produced by large doses of SCH-23390. The results suggest that D1 and D2 receptors in the nucleus accumbens could cooperate with the same adenylate cyclase and could be located on the same neurones.
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PMID:Cooperation between D1- and D2-dopamine receptors in the nucleus accumbens. 183 Jan 33

1. We studied the lactotroph cells of the rat by both in vivo and in vitro pharmacological techniques for the presence of D1-receptors. Both approaches revealed the presence of D2-receptor, stimulated by quinpirole (resulting in an inhibition of prolactin secretion) and blocked by domperidone. 2. Administration of fenoldopam, the most selective D1-receptor agonist currently available, resulted in a dose-dependent decrease of prolactin secretion in vivo (after pretreatment with alpha-methyl-p-tyrosine) and in vitro (cultured pituitary cells). This increase was dose-dependently blocked by the selective D1-receptor antagonist, SCH 23390, and although the effect of fenoldopam was less than that obtained by D2-receptor stimulation, these data suggest that a D1-receptor also controls prolactin secretion. 3. In order to detect the location of these dopamine receptors, autoradiographic studies were performed by use of [3H]-SCH 23390 and [3H]-spiperone as markers for D1- and D2-receptors, respectively. Specific binding sites for [3H]-SCH 23390 were demonstrated. Fenoldopam dose-dependently reduced [3H]-SCH 23390 binding, but had no effect on [3H]-spiperone binding. Immunocytochemical labelling of prolactin cells after incubation with [3H]-SCH 23390 revealed that the granulae and hence, D1 binding sites were present on the lactotroph cells. 4. Radioligand binding studies performed on membranes from anterior pituitary cells revealed the presence of the D2-receptor (54 fmol mg-1 protein) with a Kd of 0.58 nM for [3H]-spiperone, but failed to detect D1-receptors. 5. Finally, we studied the effect of dopamine and of fenoldopam on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content of anterior pituitary cells. Although cyclic AMP increased upon prostacyclin administration, indicating an intact adenylate cyclase system, fenoldopam failed to increase the cyclic AMP production. 6. It is tempting to speculate that fenoldopam reduces prolactin secretion through interaction with a non-cyclase-linked D1-receptor on the lactotroph cells.
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PMID:Identification of a D1 dopamine receptor, not linked to adenylate cyclase, on lactotroph cells. 183 20

l-Tetrahydroberberine-d-camphor sulfonate (THB-CS) possessed an inhibitory effect on apomorphine-induced chewing movement in a similar manner to that of tetrahydroberberine (THB). Both compounds enhanced barbiturate-induced hypnosis. They did not have an anticonvulsant effect on convulsive seizures induced by bicuculline, pentetrazole or strychnine. THB and THB-CS blocked dopamine-stimulated adenylate cyclase activity. These compounds showed almost equipotent affinities to dopamine D1 (3H-SCH-23390) and D2 (3H-spiperone) receptors but did not have significant affinity to mu-opioid, muscarinic and alpha 2-adrenergic receptors, and benzodiazepine binding sites. Furthermore, both compounds did not elicit cataleptogenic behavior, even at very high doses. These data suggest that THB and THB-CS have a central depressant effect through both D1 and D2 dopaminergic receptors and may have different modes of action from that of standard neuroleptics.
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PMID:Dopaminergic unique affinity of tetrahydroberberine and l-tetrahydroberberine-d-camphor sulfonate. 183 15

The effect of the antihypertensive drug IP66 on dopamine-induced vasodilatation has been investigated in isolated perfused rat mesenteric bed. Experiments were carried out in phenoxybenzamine-pretreated preparations to avoid the involvement of alpha-adrenoceptors. Dopamine (1-100 microM) elicited a concentration-dependent relaxation of high-K(+)-induced vasoconstriction, which was resistant to propranolol (3 microM), but antagonized by the DA1-receptor antagonist SCH 23390 (0.1 microM). However, the dopamine-vasodilating component resistant to SCH 23390 (0.1 microM) could be abolished by simultaneous administration of propranolol. Thus, dopamine-induced vasodilatation is mainly ascribable to stimulation of DA1-receptors, although an action on beta 2-adrenoceptors might contribute as well. In presence of IP66 (10 nM), dopamine-induced vasodilatation was significantly enhanced. This amplifying activity was not observed with prazosin and it was blocked by propranolol (3 microM) but unaffected by SCH 23390 (0.1 microM) or by chemical sympathectomy. Furthermore, IP66 (10 nM) also increased, in a significant manner, the amplitude of vasodilatation elicited by the beta 2-adrenoceptor agonist terbutaline, both in rat mesenteric bed and in rat aortic strips. In rat aortic membranes, IP66 (10 nM) enhanced the stimulatory effect of terbutaline (1 microM) on adenylate cyclase activity. In conclusion, IP66 is able to enhance the vasodilatation of rat mesenteric vasculature induced by dopamine or terbutaline. It is proposed that this action might be consequent to an increase in efficiency of the coupling between beta 2-adrenoceptors and membrane adenylate cyclase.
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PMID:IP66 (1[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) enhances beta-adrenoceptor-induced vasodilatation in rat mesenteric vascular bed. 196 68

Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [3H]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [3H]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (KH)- and low-affinity (KL) component. Inhibition of [3H]SCH 23390 binding in the presence of 15 microM GTP occurred with Hill slopes of unity. The KI values obtained in the presence of 15 microM GTP were similar to the KL values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.
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PMID:Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy. 197 52

The natriuretic effect of dopamine (DA) is less in younger than in older animals. The natriuretic (DA) is less in younger than in older animals. The natriuretic effect of DA is due in part to occupation of renal tubular DA1 receptors, which are most abundant in the proximal convoluted tubule (PCT). However, it has not been determined whether ontogenic differences in DA1-receptor density, affinity, or coupling to intracellular second messengers are involved in the reduced natriuretic effect of DA in the young animal. We therefore studied the DA1 receptor by radioligand binding with the DA1 antagonist 125I-SCH 23982 and the effect of DA1 agonists and guanine nucleotides on adenylate cyclase (AC) activity in microdissected PCT during development in Wistar-Kyoto rats (WKY). The dissociation constant (Kd) and maximum receptor density (Bmax) were similar in all groups (Kd, in nM: 11.9 +/- 0.7 at 3 wk, 10.6 +/- 0.4 at 8 wk, and 12.2 +/- 1.2 at 20 wk; Bmax, in fmol/mm PCT: 0.24 +/- 0.02 at 3 wk, 0.23 +/- 0.01 at 8 wk, and 0.24 +/- 0.01 at 20 wk). Basal AC activities were similar, and forskolin (10(-5) M), which directly stimulates AC, increased AC activity to a similar extent in all age groups. However, the DA1 agonists, fenoldopam (10(-5) M) and SND-919-CL2 (10(-6) M), increased AC activity in PCT to a greater extent in 20-wk-old (55 +/- 7%) than in 3-wk-old rats (27 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ontogeny of DA1 receptor-adenylate cyclase coupling in proximal convoluted tubules. 197 20

Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 micrograms 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60-70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number of affinity of D1 and D2 receptor sites. Furthermore, the appearance of DARPP-32 seems to be independent of intact DA input during development.
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PMID:Neonatal dopamine lesion in the rat results in enhanced adenylate cyclase activity without altering dopamine receptor binding or dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) immunoreactivity. 198 64

Intracerebral dialysis was used to monitor the change of extracellular concentration of striatal cAMP in rats anaesthetised with chloral hydrate. Forskolin (1-10 microM), an activator of adenylate cyclase, caused a concentration-dependent increase in efflux of cAMP, which was decreased by (+)PHNO (10 microM), an effect probably mediated by D2 sites, since (-)-sulpiride, a D2 receptor antagonist prevented these effects. Dopamine (1-100 microM) also increased the efflux of cAMP but only when the activity of monoamine oxidase and reuptake of dopamine were concomitantly blocked. The D1 receptor agonist SKF 38393 (1-100 microM) caused a concentration-dependent increase in efflux of cAMP, which was blocked by the D1 receptor antagonist SCH 23390 (1-100 microM), but was unaffected by the D2 receptor antagonist sulpiride (10 microM) or by depletion of the concentration of striatal dopamine after pretreatment with 6-hydroxydopamine. Taken together, these results indicate that intracerebral dialysis may be used to monitor the interaction of drugs with post-synaptic dopamine receptors in vivo.
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PMID:Activation of postsynaptic striatal dopamine receptors, monitored by efflux of cAMP in vivo. 198 37

To evaluate the influence of patch and matrix ingrowth of DA terminals upon striatal DA (dopamine) receptor function, we performed bilateral intrastriatal (i.s.) or single intracisternal (i.c.) injections of 6-hydroxydopamine (6-OHDA) into rat pups at various postnatal ages and determined D1 and D2 receptor binding, adenylate cyclase activities and markers for presynaptic DA terminal density and turnover as the animals matured. All injection schedules yielded: (a) variable and partial loss of DA, (b) increased DA turnover, (c) small (15-40%) increases in D1 receptor number but no change in affinity for antagonist ([3H]SCH 23390), (d) 2-3-fold increases in affinity of D1 receptors for agonist (SKF 38393) with preserved regulation of agonist affinity by guanine nucleotide, (e) no significant changes in DA-, guanine-nucleotide-, manganese- and forskolin-stimulated AC (adenylate cyclase) activity. D2 receptor binding was evaluated between 1 and 7 weeks of age in animals with i.s. treatment and 7 and 10 weeks of age in animals with i.c. treatment and was reduced by 40-50% with both treatment regimens. [3H]mazindol binding, a marker for presynaptic terminal DA transport sites, was reduced 30-40% by multiple i.s. or i.c. treatment regimens. In animals treated with one i.s. injection, [3H]mazindol binding was reduced 70% at 1 week of age, equal to control by 2 weeks and 14-46% greater than control between 3 and 7 weeks. We conclude that striatal D1 receptor sites maintain their density and second messenger function independently of postsynaptic DA terminal ingrowth, whereas the development of D2 receptor sites is sensitive to disruptions of DA terminal ingrowth.
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PMID:Postnatal development of striatal dopamine function. II. Effects of neonatal 6-hydroxydopamine treatments on D1 and D2 receptors, adenylate cyclase activity and presynaptic dopamine function. 211 42


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