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)

In an attempt to determine the mechanism by which the tripeptide l-prolyl-l-leucyl-glycine amide (PLG, MIF-I) exerts its antiparkinsonian effect, the action of this substance on various postsynaptic components of striatal dopaminergic nerves was studied. It was shown that injection of rats with MIF-I (1 mg/kg, IPX5, 24 hr intervals) did not alter tyrosine hydroxylase, dopa decarboxylase, choline acetyltransferase and glutamic acid decarboxylase activities in the striatum under the conditions tested. The activities of adenylate cyclase, dopamine-stimulated adenylate cyclase, and guanylate cyclase were not altered in vitro by various concentrations of MIF-I (0.1 to 1000 micrometer), although VIP and neurotensin had some effect. Also the rate of uptake of 3H-dopamine by rat striatal synaptosomes was unchanged, as was the binding of 3H-dopamine and 3H-spiperone to beef caudate membranes. This series of studies indicates that MIF-I does not act directly on the striatal dopamine postsynaptic receptor under the conditions tested, although it is possible that MIF-I could act indirectly at this or another site in vivo by releasing or activating some other factor.
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PMID:MIF-I and postsynaptic receptor sites for dopamine. 3 65

Proximal tubules have been shown to produce dopamine (DA) from (-)-3-(3,4-dihydroxyphenyl)-L-alanine (L-dopa) and to express DA1 dopamine (DA1) receptors linked to inhibition of sodium transport. The LLC-PK1 renal epithelial cell line expresses proximal tubule cell-like properties in vitro. Here, we sought to determine whether the LLC-PK1 cell line would be a useful model system to study dopaminergic mechanisms in vitro. LLC-PK1 cells contained high levels of aromatic L-amino acid decarboxylase (AADC) (Km 0.19 +/- 0.08 mM, Vmax 3.69 +/- 0.57 nmol.mg-1.min-1) and converted L-dopa to DA in a nonsaturable fashion up to 1 mM L-dopa. DA production was blocked by the AADC inhibitor carbidopa. Dopamine stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in LLC-PK1 cells in a dose-dependent manner (50% effective concentration, 1.53 +/- 0.38 microM; maximal stimulation, 46.6 +/- 10.88 pmol/mg protein); this effect was blocked by addition of DA1-receptor antagonists. L-Dopa also stimulated cAMP accumulation, and this effect was attenuated by an equimolar concentration of carbidopa and blocked by the DA1 antagonist Sch 23390. These results indicate that LLC-PK1 cells convert L-dopa to DA, which then stimulates cAMP via a DA1 receptor coupled to activation of adenylate cyclase. Moreover, the demonstration that locally formed DA can act as an autocrine/paracrine substance in LLC-PK1 cells in vitro is consistent with a role for DA as an autocrine/paracrine substance in vivo.
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PMID:Locally formed dopamine stimulates cAMP accumulation in LLC-PK1 cells via a DA1 dopamine receptor. 164 91

The regulation of dopamine biosynthesis in tuberoinfundibular dopaminergic (TIDA) neurons by adenosine 3',5'-cyclic monophosphate (cAMP) was investigated in the present study. Dopamine biosynthesis in TIDA neurons was estimated by the rate of in vitro dihydroxyphenylalanine (DOPA) accumulation in the median eminence of rat hypothalamic slices after incubation with a DOPA decarboxylase inhibitor. Addition of dibutyryl cAMP (db-cAMP) into medium caused an increase in the rate of DOPA accumulation in the median eminence in a dose- and time-dependent manner. 8-Bromo-cAMP also increased the rate of DOPA accumulation in the median eminence and cAMP was less effective than db-cAMP whereas neither adenosine nor sodium butyrate altered the rate of DOPA accumulation. An increase in the concentration of endogenous cAMP achieved by addition into medium of isobutylmethylxanthine, a phosphodiesterase inhibitor, or forskolin, an adenylate cyclase activator, was associated with an increase in the rate of DOPA accumulation in the medium eminence. db-cAMP, however, had an almost negligible effect on the secretion of dopamine from the median eminence. The stimulatory effect of db-cAMP on DOPA accumulation in the median eminence was not dependent upon the presence of extracellular Ca2+ and was not blocked by tetrodotoxin. Furthermore, the stimulation of DOPA accumulation in the median eminence induced by db-cAMP was additive with that induced by high potassium depolarization, which was Ca2+ -dependent. These results suggest that dopamine biosynthesis in TIDA neurons is regulated by two distinct mechanisms, one of which involves cAMP, and another of which involves Ca2+.
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PMID:Adenosine 3',5'-cyclic monophosphate stimulates dopamine biosynthesis in the median eminence of rat hypothalamic slices. 242 58

Measurements of tissue levels of monoamines and their metabolites, and of the rates of 5-hydroxytryptophan and dihydroxy-phenylalanine accumulation after blockade of aromatic amino acid decarboxylase by benserazid indicated that ipsapirone (1-10 mg/kg i.p.) decreased 5-hydroxytryptamine (5-HT) turnover and accelerated dopamine (DA) turnover in various brain regions. The reduced 5-HT turnover probably resulted from the stimulation of 5-HT1A autoreceptors within the anterior raphe nuclei as in vitro tests [( 3H]-8-hydroxy-2-[di-n-propylamino]tetralin binding and adenylate cyclase assays) demonstrated that ipsapirone was a 5-HT1A agonist almost as potent as 8-OH-DPAT, and the same decrease in 5-hydroxytryptophan accumulation could be induced by the i.p. (5 mg/kg) or intraraphe (1 microgram) injection of ipsapirone. Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT. These results demonstrate that ipsapirone-induced acceleration of DA turnover did not result from the stimulation of 5-HT1A (auto)receptors, but involved additional target(s) of the drug. The possible participation of dopaminergic systems in the "anxiolytic" properties of ipsapirone should deserve further investigations.
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PMID:Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1A agonists with potential anxiolytic properties. 245 83

A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [125I]SCH 23390) of 12.6 (4.15-38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [3H]spiroperidol is 1 290 (1,200-1,380) nM (n = 3); using [125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17,800 (9,700-32,600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5-110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF&F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses. A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.
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PMID:A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor. 250 17

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.
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PMID:Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. 378 Aug 61

Dopamine, but also other catecholamines (noradrenaline, adrenaline and isoprenaline), as well as L-dopa and alpha-methyl-dopa increase the incorporation of L-[1-3H]fucose into proteins of rat hippocampal slices. Among all substances that have been tested, dopamine exhibited the highest activity. Other non- or monohydroxylated phenylethylamine-derivatives (tyramine, octopamine, beta-phenylethylamine, metamphetamine) and pyrogallol had no effect on the fucosylation of hippocampal proteins. alpha-Methyl-dopa was less active than L-dopa. However, under the influence of alpha-methyl-dopa, an inhibitor of the dopadecarboxylase (aromatic L-amino acid decarboxylase, EC 4.1.1.28) the stimulatory effect of L-dopa on protein fucosylation was attenuated. From these results it is concluded that the dopamine-stimulated glycosylation of hippocampal proteins is triggered by (at least) two mechanisms, i.e. (1) via an activation of adenylate cyclase coupled dopamine receptor sites, and (2) via a mechanism which appears to be not related to an activation of transmitter-receptor sites but linked to the 3,4-dihydroxy-phenylethylamine-structure.
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PMID:[Dopamine-stimulated glycosylation of rat hippocampal proteins in vitro: structure-response relationship]. 409 38

The potential 5-HT1A antagonist properties of the beta-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (+/-) Tertatolol bound with high affinity (Ki = 38 nM) to 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal membranes. The (-)stereoisomer (Ki = 18 nM) was about 50-fold more potent than the (+)stereoisomer (Ki = 864 nM) to inhibit the specific binding of [3H]-8-OH-DPAT. As expected of a 5-HT1A antagonist, (-)tertatolol prevented in a concentration-dependent manner (Ki = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (-)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/kg s.c.) on the accumulation of 5-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; Ki approximately 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID50 approximately 0.40 mg/kg i.v.), (-)tertatolol prevented the inhibitory effects of the 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (-)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus)-and post (in the hippocampus)-synaptic 5-HT1A receptors in the rat brain.
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PMID:(-)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain. 768 33

We previously reported that a factor(s) from rat choriocarcinoma (Rcho-1) cells suppresses circulating PRL levels and increases tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vivo. The purposes of this study were to determine whether this factor(s) increases tyrosine hydroxylase activity in fetal hypothalamic cells in vitro and to evaluate its chemical nature. The Rcho-1 cells are of placental origin and have the capacity to differentiate into giant cells and produce members of the placental PRL family. MMQ cells, a pituitary cell line that secretes PRL, and HRP-1, a placental cell line that does not produce any known members of the PRL family, were used as control cells. Tyrosine hydroxylase activity was assessed by incubation of hypothalamic cells for 1 h with 100 microM brocresine, an inhibitor of aromatic L-amino acid decarboxylase. Tyrosine hydroxylase activity was increased in a density-dependent manner when Rcho-1, but not HRP-1 or MMQ, cells were cocultured with hypothalamic cells for 24 h. Control and Rcho-1-stimulated tyrosine hydroxylase activities were markedly reduced with 1 mM alpha-methyl-p-tyrosine, a specific inhibitor of tyrosine hydroxylase. Tyrosine hydroxylase activity was not altered when hypothalamic cells were incubated for 24 h with rat PRL or recombinant rat placental lactogen-I, whereas a 24-h stimulation with 100,000 Rcho-1 cells and a 1-h stimulation with 5 mM (Bu)2cAMP increased tyrosine hydroxylase activity 3.7- and 3-fold, respectively. The magnitudes of the increase in tyrosine hydroxylase activity were similar when hypothalamic cells were cocultured with Rcho-1 cells for 1 and 24 h. Acetic acid extracts of Rcho-1, but not HRP-1 or MMQ, cells increased tyrosine hydroxylase activity within 1 h in a concentration-dependent manner. The 3-fold increase in tyrosine hydroxylase activity observed with 500,000 Rcho-1 cell equivalents was markedly reduced with 1 mM alpha-methyl-p-tyrosine. The mol wt range of the tyrosine hydroxylase-activating factor(s) (THAF) was estimated using ultrafiltration membranes. The majority of activity was found in the eluate from a 1,000 mol wt cut-off membrane. THAF activity in Rcho-1 cell extracts was decreased by preincubation with pronase, a nonspecific proteolytic enzyme, suggesting that the factor(s) is a peptide. THAF was resistant to inactivation by trypsin or chymotrypsin pretreatment. However, both enzymes destroyed the ability of pituitary adenylate cyclase-activating peptide, either alone or with Rcho-1 cell extracts, to increase tyrosine hydroxylase activity. Oxidation of Rcho-1 cell extracts with performic acid abolished THAF activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A factor(s) from a trophoblast cell line increases tyrosine hydroxylase activity in fetal hypothalamic cell cultures. 810 May 18

The involvement of dopamine (DA) receptor subtypes in regulation of renal phosphate transport by DA, either exogenous or locally synthesized from L-dihydroxyphenylalanine (L-dopa) was evaluated in opossum kidney (OK) cells with proximal tubular phenotype. DA synthesis from L-dopa by OK cells was abolished by carbidopa and benserazide, two dissimilar inhibitors of aromatic L-amino acid decarboxylase. L-Dopa stimulated cyclic AMP generation and inhibited Na-dependent Pi uptake, and these effects were abolished by carbidopa and benserazide. The effects of L-dopa or DA on cyclic AMP generation and on Na-Pi co-transport were mimicked by SKF 38393, a DA1 receptor agonist, and were potentiated by S-sulpiride, a DA2 receptor antagonist. Bromocriptine, a DA2 receptor agonist, blunted in a pertussis toxin-dependent manner parathyroid hormone (PTH)-induced cyclic AMP generation and inhibition of Pi uptake. In contrast with PTH, neither L-dopa nor DA affected significantly the cytosolic calcium concentration. These results support the involvement of DA1 and DA2 receptors, positively and negatively coupled into adenylate cyclase respectively, in modulation of renal phosphate transport.
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PMID:Locally formed dopamine modulates renal Na-Pi co-transport through DA1 and DA2 receptors. 852 52


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