Characterization of a Dopamine‐sensitive Adenylate Cyclase in the Rat Caudate Nucleus

Clement‐Cormier, Yvonne C.; Parrish, R. G.; Petzold, Gary L.; Kebabian, J. W.; Greengard, Paul

doi:10.1111/j.1471-4159.1975.tb12241.x

Cited by 198 publications

(31 citation statements)

References 11 publications

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“…The inhibitor constant, K1, was 1.26 X 1O-7 M for acetylcholine and 5.4 X 1O-7 M for atropine; the Michaeles constant, Km for dopamnine was 2.17 X 10-9 M. The cyclase itself was not activated nor was its dopamine-induced activation increased by concentrations of atropine or acetylcholine between 0.5 and 10 juM. DISCUSSION Greengard and associates (9,19,20) have provided evidence that the adenylate cyclase studied here is a cardinal constituent of the dopaminergic receptors. The enzyme initiates postsynaptic neurotransmission and the amplification of it-in dopaminergic neurons.…”

Section: Resultsmentioning

confidence: 94%

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

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We have studied these possibilities in the hope of advancing the treatments of Parkinson's disease and of psychosis. To this end we used adenylate cyclase from mouse caudate to screen agents that can affect the symptoms of Parkinson's disease. These included drugs that stimulate the dopaminergic system in man or animals and inactive metabolites and precursors thereof and compounds that activate or inhibit the cholinergic system, which counterbalances the dopaminergic one in the brain (7,8).MATERIALS AND METHODS Animals. These were 5-to 6-week-old male Swiss albino mice, weighing 23-27 g, maintained on Purina Chow and water ad lib., and kept in an air-conditioned room on a 12-hr lightto-darkness cycle. The experiments were started in midday by decapitating the animals in a cold room. The brains were removed within 30 sec and placed on a cold watch glass. The lateral ventricles were entered by removing their roofs. The exposed heads of the caudates were scooped out with forceps.Determination of Dopamine-Stimulated Adenylate Cyclase Activity. The methods are essentially those developed in Greengard's laboratory (9). All fragments of both caudates (about 30 mg) were placed in Krebs-Ringer bicarbonate solution, pH 7.4, which had been gassed for 2 min with 5% CO2/ 95% 02. They were homogenized in 0.5 ml of 50 mM Trismaleate buffer, pH 7.4, containing 12.5 mM theophylline, 0.25 mM ethylene glycol-bis(Q-aminoethyl ether)-NN'-tetraacetic acid, and 2.5 mM MgSO4. Aliquots (0.4 ml) of the homogenates were placed in 5-ml Pyrex tubes that had previously been equilibrated to 30°in an orbital water bath. The control tubes received 50 gl of H20. The experimental tubes received different additives in different series of experiments, the concentrations of which are given below. In one series, 50 ,ul containing either dopamine or a dopaminergic substance was added. In another series, the tubesi received 25 ,ul containing one of the above substances plus 25 jul containing-an inhibitor, a metabolite, or a precursor thereof. In another series, the precursors and metabolites were tested in various concentrations for activation of the cyclase. In still another series, the metabolites were screened for inhibition of the dopamine-dependent activation. Finally, some cholinergic and anticholinergic agents were screened for activation or inhibition of the cyclase.The reaction was started by adding 50 jul of a 0.5 mM solution of ATP with mixing and then incubating in a 30°orbital water bath. After 2.5 min, the reaction was terminated by immersion of the tubes into a boiling water bath for 2 min. The homogenates were centrifuged at 1500 X g for 5 min. The supernatant solutions were quick-frozen until analyzed for adenosine 3': 5'-cyclic monophosphate (cyclic AMP) according to Gilman (10).The results of the cyclic AMP determinations were used as follows. We first computed the mean ±SEM of both nonstimulated and stimulated samples. From these we calculated the net dopamine-stimulated cyclic AMP produced by subtracting the mean nonstimulated acti...

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Section: Resultsmentioning

confidence: 94%

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

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“…However, no effect of morphine could be detected in this system. Since under the conditions described above the brain homogenate was sensitive to 10 mM NaF (usually twofold stimulation) but not to 10e3 to 10e6 M dopamine, we examined the dopamine sensitive caudate preparation described by Kebabian and colleagues [6,13] . Dopamine usually stimulated the adenylate cyclase activity of caudate homogenates with maximal effects (50-90% stimulation) occurring with 10d4 M dopamine.…”

Section: Resultsmentioning

confidence: 99%

“…We have tried to compare the effects in this preparation with those obtained in the dopamine-sensitive rat caudate homogenate [6]. Dopamine has been shown to stimulate modestly the adenylate cyclase activity of homogenates from basal ganglia [6], superior cervical ganglion [7], corpus striatum [8-lo] , cortex [ 111, retina [ 121 and nucleus accumbens and olfactory tubercle [13,14].…”

Section: Introductionmentioning

confidence: 99%

Brain and caudate nucleus adenylate cyclase: Effects of dopamine, GTP, E prostaglandins and morphine

1975

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“…of the lisuride-dependent stimulation by guanyl nucleotides: As GMP PNP (17) and GTP (16,18) were recently reported to potentiate the stimulatory action of certain substances on adenylate cyclase in a cell free system, the stimulatory effects of lisuride and apomorphine on the striatal adenylate cyclase activity were examined in the presence of these guanyl nucleotides.…”

Section: Potentiationmentioning

confidence: 99%

“…Stimulation of adenylate cyclase by various substances appears to be variable, especially in the in vitro system and, in addition, it has been clarified that certain derivatives of the guanine nucleotide such as GTP act as a modulator to facilitate coupling between the two protein moieties in the adenylate cyclase-receptor complex (16)(17)(18).…”

mentioning

confidence: 99%

Stimulatory Action of Lisuride on Dopamine-Sensitive Adenylate Cyclase in the Rat Striatal Homogenate

Azuma¹,

Oshino²

1980

Japanese Journal of Pharmacology

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Abstract-Effect of lisuride, an ergot derivative of isolysergic structure, on dopamine sensitive adenylate cyclase was studied in the homogenate of rat corpus striatum. Stimulatory action of lisuride, similar to the actions of dopamine and apomorphine, on striatal adenylate cyclase was potentiated significantly by guanosine triphosphate (GTP) and by guanyl-5'-yl imidodiphosphate (GMP-PNP), although with lisuride alone, there was only a slight stimulation.The maximal stimulation attained in the presence of GTP corresponded to about 1.4 times the basal rate of cyclic AMP formation in the homogenate and was abolished by an addition of haloperidol.Lisuride at a concentration above 3 ,uM inhibited stimulation of cyclic AMP formation by dopamine. The effect of lisuride and the extent of potentiation by the guanyl nucleotides were almost comparable to the effects of apomorphine, under corresponding conditions. Thus, lisuride, like apomorphine, acts as a partial agonist-antagonist, and has the ability to stimulate the dopamine-sensitive adenylate cyclase in the rat corpus striatum.Drugs such as apomorphine stimulate dopaminergic receptors in the brain. Lisuride, a semi-synthetic ergot derivative of isolysergic structure (1), also exhibits potent dopaminergic actions in vivo, as demonstrated by enhancement of locomotor activity (2), induction of stereotyped behavior (2) and reduction in serum prolactin levels (3). Direct stimulatory action of lisuride on dopamine receptors of post synaptic membrane was suggested by the finding that the induction of stereotyped behavior was inhibited by haloperidol, a blocker of dopamine receptors, and not by a-methyl-p-tyrosine methyl ester, an inhibitor of dopamine synthesis (2). It was also reported that specific binding of 3H-spiroperidol and of 3H-lisuride was inhibited by lisuride (4) and (+)-butaclamol (5), respectively.Adenylate cyclase in some regions of the brain is stimulated by dopamine in vitro (6-8), hence, the possibility that adenylate cyclase plays an important role in the post synaptic membrane has been discussed in relation to dopamine-dependent brain functions (9, 10).In fact, after solubilization of the synaptic membrane of bovine caudate nuclei, the enzyme activity of dopamine-sensitive adenylate cyclase could be reconstituted with two protein fractions, the one necessary for dopamine binding and the other for the catalytic site (11).Though less efficient than dopamine, apomorphine does stimulate the adenylate cyclase

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Characterization of a Dopamine‐sensitive Adenylate Cyclase in the Rat Caudate Nucleus

Cited by 198 publications

References 11 publications

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Brain and caudate nucleus adenylate cyclase: Effects of dopamine, GTP, E prostaglandins and morphine

Stimulatory Action of Lisuride on Dopamine-Sensitive Adenylate Cyclase in the Rat Striatal Homogenate

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