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)

We have previously shown that stimulation of the Ti/CD3 receptor complex on human T-cells potentiates adenylate cyclase activation by adenosine or forskolin. Anti-CD2 receptor antibodies shared with anti-CD3 antibodies the ability to potentiate dose dependently the adenosine- and forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation, whereas stimulation of the CD45 receptor had no effect on cyclase activity. Modulation of the CD3 complex with anti-CD3 antibodies was found to decrease the CD2 receptor effect on adenylate cyclase activity greatly. The possible involvement of CD3-stimulated phospholipase C (PLC) activation on the cAMP potentiation was examined using HPB-ALL cells that express a CD3 complex with a defect coupling to PLC. Stimulation of the CD3 complex on HPB-ALL cells had only slight effects on adenosine-stimulated cAMP formation, whereas the effect on forskolin-stimulated cAMP was virtually unchanged. The CD3 effect was further analyzed in Jurkat cell membranes. In contrast to the results obtained after stimulation of intact cells, it was found that OKT3 stimulation of membranes did not potentiate the forskolin response. Finally, we tested whether inhibition of endogenous adenylate cyclase agonist production affected the CD3 effect. Inhibition of adenosine production or adenosine breakdown with 8-p-sulphophenyl theophylline (8-PST) or adenosine deaminase (ADA), respectively, did not alter the CD3 effects. Indometacin, which inhibits prostaglandin production, also had no effect. Together, these data show that stimulation of the CD2 receptor potentiates adenylate cyclase responses by a mechanism that is dependent on CD3 expression. Furthermore, the CD3 effect on cAMP appears to be mediated by two different mechanisms, one which is, and one which is not dependent on PLC. Finally, this effect is not due to an endogenous production of adenylate cyclase agonists.
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PMID:CD3-dependent increase in cyclic AMP in human T-cells following stimulation of the CD2 receptor. 167 13

The ability of brown fat cells isolated from control and cold-acclimated hamsters to respond to adenosine was investigated. In measurements of the rate of oxygen consumption, it was observed that cells from control hamsters responded as expected to addition of adenosine deaminase, 3-isobutyl-1-methylxanthine (IBMX), or 2-chloroadenosine (i.e., norepinephrine dose-response curves were shifted to left in presence of adenosine deaminase or IBMX and to right with 2-chloroadenosine). However, brown fat cells isolated from cold-acclimated hamsters, under identical conditions, showed almost complete absence of adenosine control. Thus acclimation to cold induced a desensitization to adenosine by physiological means. To evaluate the molecular mechanism underlying desensitization to adenosine, [3H]phenylisopropyladenosine ([3H]PIA) binding to brown fat membranes from control and cold-acclimated hamsters was investigated. [3H]PIA bound with similar high affinity (KD approximately 5 nM) and saturability (Bmax approximately 15 fmol/mg protein) in both membrane preparations, demonstrating that desensitization to adenosine was not due to changes in adenosine receptor number or receptor affinity for adenosine. Furthermore, GTP induced a reduction in [3H]PIA affinity in brown fat membranes from both control and cold-acclimated hamsters, indicating that desensitization was probably not due to an uncoupling between the receptor and Gi protein. It was therefore concluded that the adenosine desensitization process may be located at the Gi protein-adenylate cyclase interaction.
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PMID:Cold acclimation induces desensitization to adenosine in brown fat cells without changing receptor binding. 169 90

Lipolysis in rat adipocytes is controlled by the hormonally mediated stimulation and inhibition of adenylate cyclase. This dual regulation involves stimulatory (Gs) and inhibitory (Gi) GTP-binding proteins which control cAMP production in a GTP dependent manner. Adenosine, acting via the A1 receptor-Gi complex provides tonic regulation of adenylate cyclase and lipolysis in rat adipocytes. Adipocytes prepared from young obese Zucker (fa/fa) rats exhibit less stimulation (or greater inhibition) in response to adenosine deaminase, alone or in combination with lipolytic hormones, as compared with their lean littermates. Adenylate cyclase, measured in membranes prepared from obese adipocytes, showed decreased sensitivity to activation by low concentrations of GTP and was not inhibited by higher concentrations of the guanine nucleotide which, in lean control rats results in a biphasic activity curve. Adenosine A1 receptor binding, measured in these same membranes, demonstrated an increased sensitivity to activation by the GTP analogue, guanylyl imidodiphosphate. The presence of the analogue results in the dissociation of the receptor-Gi complex and conversion to the low affinity form in a greater proportion of receptors in the obese membranes. These results are consistent with an increased sensitivity to adenosine mediated inhibition of adenylate cyclase and lipolysis in the fat cells of the young obese (fa/fa) Zucker rat.
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PMID:Winner of the 1988 NAASO Young Investigator Award. Regulation of fat cell adenylate cyclase in young Zucker (fa/fa) rats: alterations in GTP sensitivity of adenosine A1 mediated inhibition. 196 33

The effects of adenosine receptor stimulation on the contractile force of rabbit isolated left atrial preparations in the absence and presence of cAMP-generating and cAMP-independent agonists were investigated. Adenosine and the stable adenosine analogues 5'-(N-ethyl)carboxamido adenosine (NECA) and (-)-N6-phenylisopropyladenosine (R-PIA) produced a concentration-dependent direct negative inotropic effect. Responses to NECA and R-PIA were insensitive to atropine and were shifted to the right by the adenosine receptor antagonist 3-isobutyl-1-methyl xanthine (IBMX). NECA and R-PIA were found to reverse positive inotropic responses of left atria to the beta-adrenoceptor agonist, isoproterenol, but were less effective at reversing positive inotropic responses to the adenylate cyclase activator, forskolin, and were almost ineffective at reversing positive inotropic responses to alpha-adrenoceptor stimulation. Neither NECA nor R-PIA had a significant effect on basal cAMP levels or on cAMP levels elevated by isoproterenol in rabbit left atria. Similarly, R-PIA had no significant effect on basal cAMP levels or isoproterenol-induced increases in cAMP in the presence of adenosine deaminase to remove the influence of endogenous adenosine. Pretreatment of rabbits with 1.75 micrograms/kg pertussis toxin attenuated both the direct negative inotropic response of left atria to NECA and responses to NECA in the presence of isoproterenol and forskolin to a similar extent. Pretreatment of left atrial preparations with the potassium channel antagonist 4-aminopyridine resulted in a dose dependent attenuation of responses to NECA alone and in the presence of isoproterenol and forskolin. These data suggest that adenosine receptors in rabbit left atria are not coupled to adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The interaction of adenosine analogues with cAMP-generating and cAMP-independent positive inotropic agents in rabbit left atrium. 196 30

Field electrical stimulation (ES), K+ (50 mM) or ionophore X-537A (0.01 mM) induced tritium release from cat cerebral arteries preincubated with [3H]noradrenaline (NA). Adenosine and AMP (0.5 mM) did not modify tritium release caused by ionophore X-537A, but these agents and ATP (0.5 mM) significantly reduced that elicited by ES and K+; this reduction was antagonized by 1-methyl-3-isobutylxanthine (MIX; 0.05 mM). Inosine (0.5 mM) and the agonist of purinergic A2-receptors, 5'N-ethyl-carboxamide adenosine (NECA; 0.5 mM) had no effect, but the agonist of purinergic A2-receptors L-N6-phenylisopropyl adenosine (L-PIA; 0.1 mM) diminished tritium efflux caused by ES and K+. The adenosine inhibition of ES-induced radioactivity release was not affected by indomethacin (0.05 mM). MIX (0.05 mM) increased tritium release evoked by ES and K+. Agents that increase intracellular cyclic (c)AMP levels, such as dibutyryl cAMP (0.5 mM), the phosphodiesterase inhibitor Ro 20-1724 (0.1 mM), and the activators of adenylate cyclase, forskolin (0.005 mM) and NaF (2 mM) reduced tritium secretion elicited by ES and K+. However, the intracellular increase of cyclic GMP (cGMP) caused by 8-Br-cGMP did not affect this secretion. Dipyridamole (0.05 mM) and the adenosine deaminase inhibitor erythro-9-2-hydroxy-3 nonyl adenosine (EHNA; 0.1 mM) also produced inhibition of tritium secretion elicited by ES and K+. Dipyridamole reduced both the uptake of [3H]NA and [3H]adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of presynaptic purinoceptors and cyclic AMP on the noradrenaline release in cat cerebral arteries. 198 Feb 88

A1 inhibitory adenosine receptors are present in cultured Sertoli cells. Activation of these receptors by short term exposure to adenosine agonists attenuates the adenylate cyclase activity and reduces FSH stimulation of androgen aromatization to estrogen. In the present study it was investigated how long term activation of the adenosine inhibitory system affects the responsiveness of the Sertoli cell. Sertoli cells from 15- to 17-day-old Sprague-Dawley rats were incubated with medium containing adenosine deaminase (1 IU/ml) in the presence or absence of 100 nM N6-2-phenyl-isopropyl-adenosine (PIA) for 24-48 h. At the end of this pretreatment medium was changed, and cell responsiveness was measured in terms of cAMP and estrogen production. In control cells, FSH-stimulated cAMP and estradiol production were inhibited by PIA, with an EC50 of 0.70 +/- 0.13 nM. This inhibitory effect was reduced in cells that had been pretreated for 24-48 h with 100 nM PIA. The PIA concentration-response curve of pretreated cells was shifted to the right, with a 4-fold increase in the EC50. Similar effects were also evident when adenosine itself or nonmetabolizable adenosine analogs other than PIA were used in the pretreatment. In addition to these changes in the inhibitory responses, PIA pretreatment increased the response of the Sertoli cell to FSH and forskolin in terms of both cAMP accumulation and estradiol production. Potentiation of the hormonal response was due to an increase in basal and maximal stimulation without significant changes in the total stimulation. This effect was dependent on the concentration of PIA used during the pretreatment. The increase in estradiol production was also evident when cells were stimulated with (Bu)2cAMP, suggesting that adenosine analog pretreatment affects steps distal to cAMP accumulation. Moreover, the responses to both the PIA inhibitory signal and FSH stimulation were restored to control levels when pretreated cells were incubated in fresh medium in the absence of PIA for 24 h. The long term PIA effects were also blocked by pretreatment in the presence of the A1 receptor antagonist 8-[4-([([ (2-amino-ethyl)amino]carbonyl)methyl]oxy)phenyl]1,3- dipropylxanthine. These results indicate that the A1 adenosine system present in the Sertoli cell becomes refractory after prolonged exposure to adenosine analogs. Furthermore, PIA pretreatment produced a potentiation of the Sertoli cell response to stimulatory signals by affecting several steps of the cAMP-dependent pathway.
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PMID:Long term treatment with adenosine analogs modifies the responsiveness of immature rat Sertoli cell in culture. 215 62

We have examined the effects of increasing membrane polyunsaturated fatty acids (PUFAs) on adenosine receptor function in intact N1E-115 neuroblastoma cells. Addition of linoleic acid to the culture medium for 48 h resulted in an approximate threefold increase in the amount of omega 6 fatty acids esterified to membrane phospholipids. Basal cAMP accumulation was significantly higher in the PUFA-enriched cells than in controls, although the differences could be diminished by approximately 75% by treatment of the cells with adenosine deaminase or 8-phenyltheophylline. Exposure of the cultures to the stable adenosine analogue 5'-N-ethylcarboxyamide adenosine (NECA) resulted in concentration-dependent increases in cAMP accumulation. Data from saturation experiments indicated that the maximum amount of cAMP that could be formed in response to NECA in the PUFA-enriched cells was twice that in control cells. Also, the amount of agonist required to elicit half maximal stimulation in the supplemented cells was significantly less than in the control cells (mean values for EC50, 0.85 and 1.43 microM, respectively). The results of this study demonstrate that membrane PUFA have the ability to modify interactions between adenosine receptors and adenylate cyclase in neural cells, a fact that is of potential importance in considering the central role that adenosine plays as a neuromodulator in the nervous system.
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PMID:Effects of membrane polyunsaturated fatty acids on adenosine receptor function in intact N1E-115 neuroblastoma cells. 216 75

Previous results demonstrated that the adenosine that accumulates in human fat cell suspensions is derived from extracellular sources (Kather, H. (1988) J. Biol. Chem. 263, 8803-8809). To get insight into the mechanisms responsible for the lack of adenosine release, extracellular adenine nucleotide catabolism was minimized by 10 mmol/liter beta-glycerophosphate and 10 mumol/liter alpha,beta-methyleneadenosine 5'-diphosphate. Intracellular adenine nucleotide catabolism resulted in a release of inosine and hypoxanthine under these conditions that was increased markedly by isoproterenol. Experiments with inhibitors of adenosine deaminase and adenosine kinase indicated that the production of inosine and hypoxanthine proceeded via AMP deamination. Consistently, IMP levels were increased transiently in the presence of isoproterenol. In addition, the cells possessed a nucleotide phosphomonoesterase that was resistant to the inhibitory actions of ATP and alpha,beta-methyleneadenosine 5'-diphosphate and showed preference for IMP over AMP. Adenosine (approximately 1 nmol/10(6) cells/h) was also produced inside the cells. However, adenosine production was unrelated to ATP turnover via adenylate cyclase, and any adenosine formed was immediately reconverted to adenine nucleotides in the absence and presence of isoproterenol. It was concluded that adenosine is not released by intact human adipocytes, because the alternative routes of intracellular AMP catabolism are compartmentalized (at least in functional terms), and adenosine kinase is not saturated with substrate in the absence and presence of isoproterenol.
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PMID:Pathways of purine metabolism in human adipocytes. Further evidence against a role of adenosine as an endogenous regulator of human fat cell function. 229 25

This communication reports the effects of the exotoxin of Bordetella pertussis (pertussis toxin) on hamster brown fat cells. Pertussis toxin significantly increased the lipolytic and respiratory responses to isoproterenol but did not increase the basal rates of either of these processes. In contrast, the stimulation of respiration by the alpha-adrenergic agent phenylephrine was not altered by pertussis toxin. The inhibitory effects of adenosine on stimulated lipolysis, respiration, and adenylate cyclase activity were completely abolished by pertussis toxin, as was the ability of methylxanthines or adenosine deaminase to potentiate isoproterenol stimulation of respiration or lipolysis. These effects of pertussis toxin were associated with an ADP ribosylation of a single membrane protein having a molecular weight of approximately 41. These data demonstrate that pertussis toxin can prevent the inhibitory action of adenosine on brown fat cells and suggest that the effects of the nucleoside on these cells results from inhibition of adenylate cyclase. We further suggest that the enhanced responses to isoproterenol in pertussis-treated adipocytes results from a blockade of the action of endogenous adenosine. In addition to blocking adenosine action, pertussis toxin also abolished the antilipolytic effect of insulin. However, because the antilipolytic effect of insulin was prevented by adenosine deaminase and 3-isobutyl-1-methylxanthine and restored by 2-chloroadenosine, we conclude that insulin action on these cells is dependent on adenosine. Thus pertussis toxin blockade of insulin action appears to be secondary to blockade of adenosine action.
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PMID:Effects of pertussis toxin treatment on metabolism in hamster brown adipocytes. 241 1

The purine adenosine has been postulated as playing a role in CNS neurotransmission or modulation. Evidence is now provided that inhibition of adenylate cyclase in rabbit retinal homogenates is mediated via adenosine A1 receptors. Nanomolar concentrations of the A1 receptor agonists, cyclohexyladenosine (CHA) and phenylisopropyladenosine (PIA), significantly inhibited the activity of forskolin-stimulated adenylate cyclase in preparations in which endogenous adenosine was destroyed by pretreatment with adenosine deaminase. With increasing concentrations of either agonist, biphasic effects on enzyme activity were observed. The effect of the mixed A1-A2 agonist, N-ethyl-carboxamidoadenosine (NECA), on forskolin-stimulated, as well as basal adenylate cyclase, was also investigated. At micromolar concentrations, NECA significantly increased the activity of adenylate cyclase. Isobutylmethylxanthine, a potent antagonist at extracellular adenosine receptors, blocked the effects observed with PIA, CHA, and NECA. The uptake of both 3H-CHA and 3H-adenosine into retinal cells was demonstrated autoradiographically. Both agonists labeled ganglion cell bodies and certain cell bodies located in the proximal portion of the inner nuclear layer.
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PMID:Adenosine A1 receptor-mediated inhibition of adenylate cyclase in rabbit retina. 244 Oct 11


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