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 effect of aging on the binding parameters of 3H-SCH 23390, the most selective ligand of D-1 DA receptors, was studied in membrane preparations from the rat retina. DA-stimulated adenylate cyclase activity was also measured in order to better characterize the changes in retinal D-1 DA receptors induced by aging. The binding studies revealed that the density of 3H-SCH 23390 was increased (34 and 73%) in the retina of 14- and 26-month-old rats, when compared to young adult animals, respectively. In contrast, aging failed to alter the sensitivity of the adenylate cyclase to the action of DA. In fact, DA (10(-6) M to 10(-4) M) elicited a similar enhancement in cyclic AMP formation in retinal homogenates of both adult and senescent rats. Since dark adaptation increases the density of D-1 DA receptors in the retina of adult rats we studied the effect of light deprivation on 3H-SCH 23390 binding and DA-sensitive adenylate cyclase activity in the retina of senescent rats. As previously shown (25) light deprivation increased 3H-SCH 23390 binding and enhanced DA-sensitive adenylate cyclase activity in the retina of young adult rats. On the contrary, dark adaptation failed to increase 3H-SCH 23390 binding and to enhance DA-sensitive adenylate cyclase activity in the retina of senescent rats. Taken together these results indicate that D-1 DA receptors in the retina of aged rats have biochemical and functional properties different from those found in the retina of adult animals; these changes may result in an altered response to the physiological stimuli elicited by environmental lighting.
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PMID:Failure of dark adaptation to upregulate D-1 dopamine receptors in retina of senescent rats. 219 Jan 5

In the presence of SCH 23390, a potent blocker of D1 dopamine receptors, dopamine inhibits adenylate cyclase activity of synaptic plasma membranes isolated from rat striatum. Maximal inhibition corresponds to a 20-25% decrease of basal enzyme activity and is reached with 100 microM dopamine. The apparent IC50 of dopamine is 2.5 microM. The inhibitory effect of dopamine is mimicked by various dopamine receptor agonists with the following rank order of potency: (-)-propylnorapomorphine greater than or equal to bromocriptine greater than (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene = (-)-apomorphine greater than dopamine greater than LY 171555 greater than l-noradrenaline greater than l-phenylephrine. Clonidine and l-isoproterenol are inactive at 100 microM. Bromocriptine and LY 171555, two agents which stimulate selectively D2 receptors, inhibit striatal adenylate cyclase activity in the absence of SCH 23390. However, bromocriptine behaves like a partial agonist. A variety of neuroleptic drugs antagonize the dopamine inhibition with a rank order of potency which qualitatively correlates with their relative affinity for D2 receptors. l-Sulpiride (EC50 = 210 nM) and (+)-butaclamol (EC50 = 130 nM) are severalfold more potent than d-sulpiride (EC50 = 5 microM) and (-)-butaclamol (EC50 = 10 microM). The inhibitory effect of dopamine on striatal adenylate cyclase activity is dependent on the presence of GTP, with half-maximal inhibition occurring at 1 microM GTP. In the absence of SCH 23390, dopamine stimulates adenylate cyclase activity, reaching a maximum at 1 microM GTP. At higher concentrations of the nucleotide, the dopamine-stimulated enzyme activity decreases, and this decline is antagonized by the D2 receptor blocker l-sulpiride. Guanyl-5'-yl imidodiphosphate, a stable analogue of GTP, has a biphasic effect on the striatal adenylate cyclase activity, inhibiting at low concentration (from 1 to 100 nM) and stimulating at higher concentrations. Selective activation of D2 receptors by LY 171555 does not increase the extent of enzyme inhibition elicited by guanyl-5'-yl imidodiphosphate. Sodium chloride amplifies the inhibition of striatal adenylate cyclase activity by LY 171555 and reduces the potency of the D2 agonist by a factor of 4. The dopamine-inhibited enzyme activity is lost following intrastriatal injection of kainic acid. The results indicate that in rat striatum dopamine inhibits adenylate cyclase activity by acting on postsynaptic dopamine receptors with pharmacological properties of D2 type.
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PMID:Characterization of dopamine receptors mediating inhibition of adenylate cyclase activity in rat striatum. 241 Jul 69

Methods for measuring 3H-SCH 23390 binding and dopamine (DA) stimulated adenylate cyclase (AC) were established in identical tissue preparations and under similar experimental conditions. Pharmacological characterization revealed that both assays involved interaction with the D1 receptor or closely associated sites. In order to investigate whether the binding sites for 3H-SCH 23390 and DA in fact are identical, the antagonistic effects of a variety of pharmacologically active compounds were examined. Surprisingly, the Ki-values obtained from Schild-plot analysis of the antagonism of DA-stimulated AC, were 80-240 times higher than the Ki-values obtained from competition curves of 3H-SCH 23390 binding. Since both assays were performed under identical conditions, the differences in Ki-values indicate the possibility of different binding sites for DA and 3H-SCH 23390 or, that DA and 3H-SCH 23390 label different states of the same receptor.
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PMID:A comparison between dopamine-stimulated adenylate cyclase and 3H-SCH 23390 binding in rat striatum. 241 93

Measuring adenylate cyclase activity (AC) as a biochemical index of dopamine (DA) receptor function, we obtained evidence for the presence in rabbit vasculature of both D1 receptors associated with stimulation of AC and of D2 receptors coupled with AC in an inhibitory way. The cAMP generating system in rabbit mesenteric artery was stimulated by DA and several DA agonists, an effect antagonized by the D1-receptor blocker SCH 23390 and by other neuroleptic drugs. When activation of D1 sites was impeded by SCH 23390, DA, (-)apomorphine, and (-)NPA inhibited cAMP formation. In addition, selective D2 agonists inhibited basal AC activity even when there was no D1-receptor blockade. The relative order of potency of various neuroleptics in antagonizing bromocriptine-induced inhibition of AC confirmed the D2 nature of these binding sites. Inhibition of AC activity elicited by bromocriptine remained unchanged after chemical sympathectomy, suggesting that vascular D2 receptors inhibiting AC activity are located postsynaptically in the arterial wall.
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PMID:Identification and characterization of postsynaptic D1- and D2-dopamine receptors in the cardiovascular system. 245 58

3,4-Dihydroxyphenylethylamine (dopamine) and beta-adrenergic receptor agonists and antagonists were assessed for their effects on cyclic AMP accumulation in human astrocytoma derived clone D384 cells. Dopamine, SKF 38393, and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene increased cyclic AMP content with Ka values of 2.0, 0.2, and 1.6 microM. The D1-selective antagonists SCH 23390 (Ki, 1.2 nM) and SKF 83566 (Ki, 0.8 nM) were over 5,000-fold more potent than the D2-selective antagonist domperidone (Ki, 6.7 microM) at inhibiting dopamine stimulation of cyclic AMP formation. SCH 23388 (Ki, 560 nM; the S-enantiomer of SCH 23390) was 400-fold less potent than SCH 23390. Isoprenaline, adrenaline, salbutamol, and noradrenaline increased cyclic AMP content with Ka values of 0.13, 0.12, 0.22, and 7.60 microM. The beta 2-selective antagonist ICI 118,551 (Ki,0.8 nM) was almost 8,000-fold more potent than the beta 1-selective antagonist practolol (Ki, 5.9 microM) at inhibiting isoprenaline stimulated cyclic AMP accumulation. These results demonstrate that D384 cells express D1-dopamine and beta 2-adrenergic receptors linked to adenylate cyclase. Furthermore, the dopamine receptor expressed by D384 cells exhibits a pharmacological profile typical of a mammalian striatal D1-receptor and therefore the use of this clone represents another approach to studying central D1-receptors.
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PMID:Characterization of dopamine and beta-adrenergic receptors linked to cyclic AMP formation in intact cells of the clone D384 derived from a human astrocytoma. 245 12

The dopamine (DA) D-1 and D-2 receptors coupled to adenylate cyclase in the rat retina were characterized pharmacologically. In confirmation of reports using other neural tissues, activation of D-1 receptors with DA, apomorphine or SKF 38393 resulted in activation of adenylate cyclase and enhanced accumulation of cyclic AMP (cAMP). The response to DA was blocked by SCH 23390, a D-1 receptor antagonist. D-2 receptors negatively coupled to adenylate cyclase were demonstrated by preincubating retina with SCH 23390 and then with DA or apomorphine. D-2 receptor responses were also elicited with quinpirole or bromocriptine, D-2 receptor agonists, in the absence of SCH 23390. (+)-Butaclamol, but not (-)-butaclamol, blocked the D-2 receptor-induced decrease of cAMP. Moreover, I-sulpiride was more active than d-sulpiride in reversing the DA-induced inhibition of cAMP accumulation. D-1 and D-2 receptor responses were also evident in forskolin-activated retina. The intraocular injection of pertussis toxin prevented the fall of cAMP and enhanced the rise of cAMP by DA, indirectly implicating the need for a guanine nucleotide regulatory protein in the process. Our results demonstrate that retinal tissue contains DA receptors that are similar to those found in brain and they imply that therapeutic agents that interact with the receptors in brain might interact with the receptors in retina.
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PMID:Pharmacological characterization of rat retinal dopamine receptors. 249 95

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

The presence of D1 dopamine receptors in the parathyroid gland has been proposed based on the demonstration of dopaminergic regulation of adenylate cyclase activity and parathyroid hormone release in dispersed bovine parathyroid cells. Using a radioiodinated D1 selective antagonist [125I]-SCH 23982, we have now directly labeled and characterized the D1 dopamine receptors in bovine parathyroid gland membranes. [125I]-SCH 23982 binds in a saturable manner with high affinity and low nonspecific binding to membranes prepared from bovine parathyroid glands. D1 dopamine receptors are present in this preparation at a concentration of approximately 130 fMoles/mg protein and [125I]-SCH 23982 binding increases with increasing protein concentration in a linear fashion. Determination of the Kd using the association (k1) and dissociation (k-1) rate constants revealed good agreement with the Kd determined by saturation analysis (390 pM vs. 682 pM, respectively). Inhibition of 0.3 nM [125I]-SCH 23982 binding by a series of dopaminergic antagonists verified the D1 nature of this binding site, exhibiting appropriate affinities and rank order of potency. The competition curves of all antagonists exhibited Hill coefficients that were not significantly different from 1. Inhibition of [125I]-SCH 23982 binding by dopamine and other dopaminergic agonists revealed the presence of high and low affinity agonist binding sites. Addition of 200 microM GppNHp effected a complete conversion of high affinity dopamine binding sites to a homogeneous population of low affinity dopamine sites. The D1 receptors identified in the parathyroid gland with [125I]-SCH 23982 appear to be pharmacologically identical with those previously characterized in the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Direct demonstration of D1 dopamine receptors in the bovine parathyroid gland using the D1 selective antagonist [125I]-SCH 23982. 252 16

Experiments have been conducted to determine whether dopamine fulfills the criteria to be considered as a neurotransmitter in cat primary visual cortex. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a neurotoxin with high selectivity for noradrenergic terminals, was administered into kitten cerebral ventricles. Two weeks later, the concentration of norepinephrine in visual cortex was reduced to 15% of control while dopamine and serotonin were not depleted. Receptor binding assays with [3H]SCH 23390 showed that membranes prepared from cat primary visual cortex contain a binding site that has the properties of a D1 receptor. This site was localized by autoradiography to two bands, one in layer VI and the second in upper layers of visual cortex. A dopamine-stimulated adenylate cyclase activity was demonstrated that was inhibited by SCH 23390 but not by alprenolol. Norepinephrine was shown to stimulate adenylate cyclase activity through both a beta-noradrenergic receptor and a D1 receptor. Binding assays with [3H]spiperone indicated that D2 dopamine receptors are absent from cat visual cortex or present in very low amounts. Taken together these results strongly suggest the existence of a dopamine innervation of cat primary visual cortex. The neurotoxin experiments show that some of the dopamine in cat visual cortex is not in noradrenergic terminals while the receptor assays demonstrate the presence of D1 receptors functionally linked to the synthesis of cyclic 3',5'-adenosine monophosphate. The demonstration of a dopaminergic innervation in cat primary visual cortex is also relevant to the interpretation of data on the involvement of catecholamines in developmental plastic phenomena.
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PMID:Evidence for a dopaminergic innervation of cat primary visual cortex. 252 5

Dopamine reduces the stimulation of intracellular [3H]arachidonate release produced by the two PRL-stimulating peptides angiotensin-II and TRH. This effect is concentration dependent and is mediated by stimulation of D-2 dopamine receptors. D-2 receptor agonists (bromocriptine, dihydroergocryptine, and dihydroergocristine) inhibit the release of fatty acid induced by angiotensin-II with a potency that parallels their ability to inhibit PRL release in vitro. Conversely, the selective D-2 receptor antagonist L-sulpiride completely prevents dopamine's effect, whereas SCH 23390 (a D-1 receptor antagonist) is ineffective. The inhibitory action of dopamine does not seem to be consequent to an action on the adenylate cyclase-cAMP system, as 8-bromo-cAMP (1 mM) does not affect either basal or dopamine-inhibited [3H]arachidonate release. However, a 24-h pertussis toxin pretreatment significantly reduces the action of dopamine on fatty acid release. Collectively, these results suggest that D-2 dopamine receptor-mediated inhibition of intracellular [3H]arachidonate release requires the action of a GTP-binding protein, but is not a consequence of an inhibitory action on cAMP levels.
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PMID:D-2 dopamine receptor activation reduces free [3H]arachidonate release induced by hypophysiotropic peptides in anterior pituitary cells. 252 49


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