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

Tell, G.; Pasternak, Gavril W.; Cuatrecasas, Pedro

doi:10.1016/0014-5793(75)80896-9

Cited by 44 publications

(14 citation statements)

References 28 publications

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“…1972). In contrast t o the results of Tell et a/. (1975), a n d Schmidt & Way (1976) on similar preparations the cyclase could also be stimulated with prostaglandins El and Ez (table 1).…”

Section: Discussioncontrasting

confidence: 56%

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Adenylate Cyclase in Rat Synaptosomal Plasma Membranes and Caudate Nucleus Homogenate: Effects of Dopamine, E Prostaglandins, Guanyl‐5′‐yl‐imidodiphosphate and Morphine

Grynne

1982

Acta Pharmacologica et Toxicologica

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The adenylate cyclase in two particulate preparations from rat brain, a homogenate from caudate nucleus (CN‐homogenate) and a synaptosomal plasma membrane fraction (SPM‐fraction) from whole rat brain was investigated. Stimulation of the enzyme by dopamine and prostaglandins E1 and E2 was found in the CN‐homogenate while only a weak prostaglandin E1 and E2 stimulation and no dopamine stimulation could be found in the SPM‐fraction. Guanyl‐5′‐yl‐imidophosphate (GppNHp) and NaF could stimulate the adenylate cyclase in both preparations. Morphine up to 10–5 M altered neither the basal enzyme activity nor any of the stimulated enzyme activities.

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“…1972). In contrast t o the results of Tell et a/. (1975), a n d Schmidt & Way (1976) on similar preparations the cyclase could also be stimulated with prostaglandins El and Ez (table 1).…”

Section: Discussioncontrasting

confidence: 56%

“…Several authors have studied the effect of morphine or other opiates in combination with dopamine or prostaglandins El and EZ on adenylate cyclase in rat brain hornogenates. (Schmidt & Way 1976;Motomatsu et al 1977;Tell et al 1975;Puri et al 1975;Govoni et al 1975;Badger & Cicero 1977;Inwegen et ul. 1975: Iwatsubo 1977Collier & Roy 1974).…”

Section: Discussionmentioning

confidence: 99%

Adenylate Cyclase in Rat Synaptosomal Plasma Membranes and Caudate Nucleus Homogenate: Effects of Dopamine, E Prostaglandins, Guanyl‐5′‐yl‐imidodiphosphate and Morphine

Grynne

1982

Acta Pharmacologica et Toxicologica

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“…First, Jacobs (40) has shown that a-adrenergic inhibition of human platelet adenylate cyclase is dependent on GTP. Second, Tell et al (41) found that, in order to elicit activation of caudate nucleus cyclase with dopamine, the enzyme first had to be inhibited with GTP; dopamine then reversed this inhibition. These examples, plus the data in this paper, suggest that GTP-mediated inhibition of adenylate cyclases may be of physiologic importance.…”

Section: Discussionmentioning

confidence: 99%

Adenosine analogs inhibit adipocyte adenylate cyclase by a GTP-dependent process: basis for actions of adenosine and methylxanthines on cyclic AMP production and lipolysis.

Londos¹,

Cooper²,

Schlegel³

et al. 1978

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

224

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ABSTRACr Adenylate cyclase in purified membranes from rat adipocytes is inhibited by low concentrations of purinemodified adenosine analogs, particularly those modified in the NO position. Such inhibition is antagonized competitively by methylxanthines, but not by other cyclic nucleotide phosphodiesterase inhibitors, and it is dependent on "inhibitory" concentrations of GTP in the assay medium. Ribose-modified adenosine analogs inhibit adenylate cyclase-through a process that is neither dgepndent upon the GTP concentration nor antagonized by MeThylxanthines. These results explain the potent ef of adenosine and methylxanthines on fat cell metabolism and demonstrate the importance of GTP in mediating inhibition by agents that act at cell surface receptors. Two distinct sites through which adenosine alters adenylate cyclase activity in plasma membrane preparations have been identified with the use of adenosine analogs (1). One site mediates inhibition in all cases thus far described and accepts, as agonists, adenosine analogs modified in the ribose moiety, such as 2',5'-dideoxyadenosine and 9-.f-D-arabinofuranosyladenine. This site does not react with several purine-modified analogs and, based on the requirement for integrity of the purine moiety, has been designated the P site. The other site, termed R, does not react with most ribose-modified analogs but accepts purine-modified compounds such as N6-phenylisopropyladenosine, N6-methyladenosine, and 2-methyladenosine. In all cases described thus far, the R site mediates activation of adenylate cyclase. Methylxanthines, such as theophylline, antagonize the activating effects of adenosine at the R site but have no effect on the P site. These generalizations are based on a comparison of our direct examination of several adenylate cyclases (1) with numerous published reports on the effects of adenosine and adenosine analogs on cyclic AMP accumulation in intact cells and on adenylate cyclase activity (2-17, plus others cited in ref. 1).The rat adipocyte presents a paradox with regard to the effects of adenosine analogs in that both P and R site-reactive compounds depress cyclic AMP accumulation-in the intact cell (18)(19)(20). P site effectors, such as 2',5'-dideoxyadenosine, depress adenylate cyclase activity in isolated membrane preparations (18,19,21 This study shows that GTP plays an essential role in the expression of R site-mediated inhibition of adenylate cyclase activity in adipocyte plasma membranes. With the fat cell enzyme, GTP exerts both stimulatory and inhibitory effects (23-26) that appear to be expressed through different processes (26). Our data show that inhibition by R site analogs is linked to the GTP inhibitory process, occurs with those analogs that potently inhibit cyclic AMP formation and lipolysis in fat cells, and is antagonized by methylxanthines. These findings can explain the potent inhibitory effects of adenosine on fat cell metabolism and the stimulatory effects of methylxanthines on cyclic AMP formation and lipolysis. MATERIALS AND METHOD...

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“…Recent observations with neuroblastoma X glioma hybrid cells indicate that the binding of morphine and other opiates to narcotic receptors results in an inhibition of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity (1-3) and a decrease in cAMP levels in intact cells (1,2,4,5). Similar observations have been made with brain (6,9) but the heterogeneity of cell types present and apparent lability of the brain enzyme may be responsible for conflicting observations (8)(9)(10). Both dependence upon opiates and tolerance to these compounds were hypothesized to result from either an increase in the number of molecules of adenylate cyclase or a long-lived factor which affects the rates of adenylate cyclase activity or turnover (1).…”

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confidence: 92%

Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance.

Sharma¹,

Klee²,

Nirenberg³

1975

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

562

275

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Narcotics affect adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.8.1.1J in two opposing ways, both mediated by the opiate receptor. The first process is the readily reversible inhibition of the enzyme by narcotics; the second is a compensatory increase in enzyme activity which is delayed in onset and relatively stable. Late positive regulation of the enzyme counteracts the inhibitory influence of morphine and is responsible for narcotic dependence and tolerance. The coupled inhibitory and positive regulatory mechanisms for adenylate cyclase provide a means of activating and deactivating neural circuits hours after the initial event and thus may play a role in a memory process. Recent observations with neuroblastoma X glioma hybrid cells indicate that the binding of morphine and other opiates to narcotic receptors results in an inhibition of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity (1-3) and a decrease in cAMP levels in intact cells (1, 2, 4, 5). Similar observations have been made with brain (6, 9) but the heterogeneity of cell types present and apparent lability of the brain enzyme may be responsible for conflicting observations (8)(9)(10). Both dependence upon opiates and tolerance to these compounds were hypothesized to result from either an increase in the number of molecules of adenylate cyclase or a long-lived factor which affects the rates of adenylate cyclase activity or turnover (1). In this report, we describe the results of experiments which were designed to test the hypothesis illustrated diagramatically in Fig. 1. The addition of morphine results in the rapid inhibition of adenylate cyclase activity and a resultant decrease in intracellular cAMP levels. Further incubation reveals a second regulatory process which involves a compensatory increase in adenylate cyclase activity termed late positive regulation. The increase in adenylate cyclase activity counteracts the inhibition of enzyme activity by morphine and cAMP levels are restored to the normal value. Cells now are tolerant to morphine and are also dependent upon the narcotic, since withdrawal of the drug or the addition of a specific narcotic antagonist will raise cAMP levels to abnormally high values and secondarily produce a gradual return to the normal level of adenylate cyclase activity.In this communication we report data which demonstrate a rapid inhibition and a late positive regulation of adenylate cyclase which are dependent upon narcotics and account for the phenomena of narcotic dependence and tolerance. METHODS AND MATERIALSThe source of each chemical and the medium and growth conditions for neuroblastoma X glioma hybrid NG108-15 were described previously (1).Assay of cAMP in Intact Cells and Medium. Growth medium was changed 12 hr before assay. Narcotic was added to the growth medium [Dulbecco's modification of Eagle's medium (DMEM), hypoxanthine-aminopterinthymidine (HAT), and 10% fetal bovine serum] and plates were incubated in a humidified atmosphere of 90% air-10% C02. A...

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

Cited by 44 publications

References 28 publications

Adenylate Cyclase in Rat Synaptosomal Plasma Membranes and Caudate Nucleus Homogenate: Effects of Dopamine, E Prostaglandins, Guanyl‐5′‐yl‐imidodiphosphate and Morphine

Adenylate Cyclase in Rat Synaptosomal Plasma Membranes and Caudate Nucleus Homogenate: Effects of Dopamine, E Prostaglandins, Guanyl‐5′‐yl‐imidodiphosphate and Morphine

Adenosine analogs inhibit adipocyte adenylate cyclase by a GTP-dependent process: basis for actions of adenosine and methylxanthines on cyclic AMP production and lipolysis.

Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance.

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