Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mixed adrenergic agonist epinephrine, at a 10 microM concentration, stimulated cyclic AMP production and glycerol release in the epididymal adipose tissue of ob/ob male mice. These effects when tested, respectively, after 7 min in the presence and after 60 min in the absence of theophylline were, however, 7- and 5-fold lower than in lean controls. The alpha-adrenergic blocker phentolamine and adenosine deaminase (which destroys extracellular adenosine) did not restore a normal lipolytic response to epinephrine in the adipose tissue of ob/ob mice. These data provide indirect evidence against a hyperactive mechanism in the coupling of alpha-adrenergic receptors and adenosine receptors to Ni, the guanine nucleotide-binding inhibitory component of adenylate cyclase, as the cause of reduced lipolysis in the adipose tissue of ob/ob mice.
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PMID:Indirect evidence against a contribution of the guanine nucleotide-binding inhibitory component of adenylate cyclase to impaired lipolysis in the epididymal adipose tissue of congenitally obese (ob/ob) mice. 299 42

The effects of adenosine receptor agonists and antagonists were examined in epithelia formed in culture by A6 cells, a continuous cell line derived from Xenopus laevis kidney. A6 epithelia have a high electrical resistance and a short-circuit current that is equal to net sodium flux from mucosal to serosal surface. Adenosine, 2-chloroadenosine, 5'-(N-ethyl)carboxamidoadenosine, and N6-(L-2-phenylisopropyl) adenosine produced concentration-dependent increases in short-circuit current. Stimulation of short-circuit current by 2-chloroadenosine occurred at concentrations of 0.05 microM and above, with half-maximal stimulation occurring at 0.3 microM. 5'-(N-ethyl)carboxamidoadenosine was more potent than N6-(L-2-phenylisopropyl)adenosine, the usual order of potency for activation of stimulatory adenosine receptors. Theophylline (100 microM), an adenosine receptor antagonist, reduced the short-circuit current response to adenosine and 2-chloroadenosine by 85-90%. Amiloride, an agent that inhibits both basal and adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated short-circuit current in A6 epithelia, completely and reversibly inhibited short-circuit current stimulated by 2-chloroadenosine. Adenosine and 2-chloroadenosine stimulated adenylate cyclase activity in a crude membrane preparation from A6 cells. Stimulation by adenosine was blocked by adenosine deaminase. 2-Chloroadenosine increased cell cAMP accumulation in intact epithelia. The results provide evidence that adenosine and adenosine receptor agonists stimulate adenylate cyclase and active sodium transport in an epithelial cell line of renal origin.
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PMID:Adenosine stimulates sodium transport in kidney A6 epithelia in culture. 299 88

The effects of adenosine deaminase and of pertussis toxin on hormonal regulation of lipolysis were investigated in isolated human fat cells. Adenosine deaminase (1.6 micrograms/ml) caused a two-to threefold increase in cyclic AMP, which was associated with an increase in glycerol release averaging 150-200% above basal levels. Clonidine, N6-phenylisopropyladenosine, prostaglandin E2, and insulin caused a dose-dependent inhibition of glycerol release in the presence of adenosine deaminase. Pretreatment of adipocytes with pertussis toxin (5 micrograms/ml) for 180 min resulted in a five- to sevenfold increase in cyclic AMP. Glycerol release was almost maximal and isoproterenol caused either no further increase or only a marginal additional increase of lipolysis after pretreatment with pertussis toxin, whereas cyclic AMP levels were 500 times higher than in controls. The effects of antilipolytic agents known to affect lipolysis by inhibition of adenylate cyclase activity, i.e., clonidine, N6-phenylisopropyladenosine, and prostaglandin E2, were impaired. In contrast, the antilipolytic action of insulin was preserved in adipocytes pretreated with pertussis toxin. As in controls, the peptide hormone had no detectable effect on cyclic AMP after pertussis toxin treatment. The findings support the view that the antilipolytic effect of insulin does not require adenylate cyclase or phosphodiesterase action. In addition, the results demonstrate that, upon relief of endogenous inhibition, human fat cell lipolysis proceeds at considerable (adenosine deaminase) or almost maximal (pertussis toxin) rates. A certain degree of inhibition, therefore, appears to be necessary for human fat cell lipolysis to be susceptible for hormonal activation.
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PMID:Human fat cell lipolysis is primarily regulated by inhibitory modulators acting through distinct mechanisms. 299 84

Micromolar concentrations of adenosine and its analogs have profound depressant effects on neuronal firing and synaptic transmission in many brain areas. Using the adenosine agonist 2-chloro[3H]adenosine (Cl[3H]Ado), we have identified a distinct class of micromolar-affinity adenosine binding sites in rat forebrain membranes. Specific Cl[3H]Ado binding was reversible and saturable with an apparent KD of 9.1 microM and a Bmax of 61 pmoles/mg protein. The present studies were conducted using washed brain membrane fractions not treated with adenosine deaminase. Specific Cl[3H]Ado binding under these conditions was insensitive to (-)-N6-(R-phenylisopropyl)adenosine ((-)PIA) and treatment with 3 mM N-ethylmaleimide, unlike high-affinity A1 adenosine receptor binding. Treatment of membranes with adenosine deaminase revealed an additional population of binding sites sensitive to (-)PIA. Inhibition of Cl[3H]Ado binding by adenosine analogs exhibited an order of potency ClAdo greater than 5'-N-ethylcarboxamide adenosine (NECA) greater than (-)PIA which differs from that of both A1 and A2 adenosine receptors. The potent A1 and A2 receptor antagonist 8-phenyltheophylline had no significant effect on binding up to 10 microM. Specific binding, however, was inhibited by the adenosine antagonists 8(p-sulfophenyl)theophylline, isobutylmethylxanthine, theophylline, and caffeine. Micromolar Cl[3H]Ado binding was highly selective for adenosine agonists and antagonists. These results suggest that the micromolar-affinity Cl[3H]Ado binding sites may represent a novel central purinergic receptor, distinct from the A1 and A2 adenosine receptors involved in the regulation of adenylate cyclase.
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PMID:A new class of adenosine receptors in brain. Characterization by 2-chloro[3H]adenosine binding. 300 93

A sensitive, reproducible assay for adenylate cyclase is described which separates labeled cyclic AMP from ATP and other nucleotides by high-performance liquid chromatography (HPLC) on reverse-phase columns. The technique utilizes [3H]ATP as substrate, and the principal compound contaminating the [3H]cyclic AMP peak, adenosine, is removed by incubation of assay tubes with small amounts of adenosine deaminase. The HPLC elution utilizes high resolution (3 microns) short (10 cm) C-18 columns for increased resolution and decreased flow rates. Since cyclic AMP elutes at 4 min following injection, this procedure can easily process large numbers of samples per day when combined with automated techniques of sample injection and collection.
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PMID:A high-performance liquid chromatography assay of brain adenylate cyclase using [3H]ATP as substrate. 301 Jan 45

Adipocytes from hypothyroid rats have a decreased responsiveness to agents that activate adenylate cyclase, whereas cells from hyperthyroid rats have an increased responsiveness as compared to the controls. This is reflected in cyclic AMP accumulation as well as lipolysis. Administration of pertussis toxin to rats or its in vitro addition to adipocytes increased basal lipolysis and cyclic AMP accumulation as well as the response to norepinephrine or forskolin. The effects of thyroid status was not abolished by toxin treatment. Pertussis toxin-catalyzed ADP ribosylation of Ni was increased in adipocyte membranes from hypothyroid rats as compared to those from euthyroid rats. However, no change in sensitivity to N6-(phenylisopropyl)adenosine was observed. The data suggest that the amount of Ni might not be rate-limiting for the inhibitory action of adenosine. A consistent decrease in maximal lipolysis was observed in freshly isolated adipocytes from hypothyroid animals as compared to those from the controls. Such defective maximal lipolysis was not corrected by adenosine deaminase or in vivo administration of pertussis toxin. The relationship between cyclic AMP levels and lipolysis suggests that in fat cells from hypothyroid rats either the cyclic AMP-dependent protein kinase or the lipase activity itself may limit maximal lipolysis. There appears to be multiple effects of thyroid status on lipolysis involving factors other than those affecting adenylate cyclase activation.
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PMID:Pertussis toxin effects on adenylate cyclase activity, cyclic AMP accumulation and lipolysis in adipocytes from hypothyroid, euthyroid and hyperthyroid rats. 301 Nov 6

Endogenous adenosine acting via A1 adenosine receptors is capable of inhibiting adenylate cyclase activity and neurotransmitter release in the brain. In this report, we describe the synthesis and attributes of a new series of A1 adenosine receptor agonists. One of these, [125I]N6-2-(4-amino-3-iodophenyl)ethyladenosine, can be used as a radioligand and another, [125I]N6-2-(4-azido-3-iodophenyl)ethyladenosine, as a photoaffinity probe. The unlabeled ligand, N6-2-(4-aminophenyl)ethyladenosine, and its iodinated product are full agonists, inhibiting cyclic AMP production in rat cerebral cortex membranes to the same extent as the prototypic A1 agonist N6-R-1-phenyl-2-propyladenosine. These new ligands are not substrates for adenosine deaminase. The new photoaffinity azide described here labels an Mr 38,000 protein that displays all the pharmacological characteristics expected of the A1 adenosine receptor. This is the same molecular-weight protein previously described using a cross-linking radioligand. This new azide compound demonstrates a 15-fold higher efficiency of incorporation, making it the photoaffinity probe of choice for tissues containing low concentrations of A1 adenosine receptors.
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PMID:Characterization of the A1 adenosine receptor-adenylate cyclase system of cerebral cortex using an agonist photoaffinity ligand. 301 53

This paper examines the modulation of insulin-stimulated glucose transport activity in rat adipose cells by ligands for receptors (R) that mediate stimulation (Rs; lipolytic) or inhibition (Ri; antilipolytic) of adenylate cyclase. The changes in glucose transport activity and cAMP, as assessed by 3-O-methylglucose uptake and (-/+) cAMP-dependent protein kinase (A-kinase) activity ratios, respectively, were monitored under conditions that maintain steady-state A-kinase activity ratios (Honnor, R. C., Dhillon, G. S., and Londos, C. (1985) J. Biol. Chem. 260, 15122-15129). Removal of endogenous adenosine with adenosine deaminase decreased insulin-stimulated glucose transport activity by approximately 30%, which was prevented or restored with Ri agonists such as phenylisopropyladenosine, nicotinic acid, and prostaglandin E1. These changes in transport activity were not accompanied by changes in A-kinase activity ratios, indicating that Ri-mediated effects on transport are independent of cAMP changes. Addition of an Rs ligand, isoproterenol, in the presence of adenosine increased kinase activity but did not change glucose transport activity. Conversely, upon removal of adenosine, addition of Rs ligands such as isoproterenol, adrenocorticotropic hormone, or glucagon strongly inhibited transport (approximately 50%) and stimulated kinase activity. However, subsequent addition of phenylisopropyladenosine nearly restored transport activity without alteration of A-kinase activity. These data and additional kinetic experiments suggest that Rs-mediated glucose transport modulations are also independent of cAMP. The interchangeability of ligands for both Rs and Ri receptors in modulating transport activity suggests that these cAMP-independent effects are mediated by the stimulatory (Ns) and inhibitory (Ni) guanyl nucleotide-binding regulatory proteins of adenylate cyclase. All Rs-and Ri-induced changes in transport activity occurred without a change in glucose transporter distribution, as assessed by D-glucose-inhibitable cytochalasin B binding, suggesting that Rs and Ri ligands modulate the intrinsic activity of the glucose transporter present in the plasma membrane.
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PMID:Regulation of insulin-stimulated glucose transport in the isolated rat adipocyte. cAMP-independent effects of lipolytic and antilipolytic agents. 302 4

The effects of short-term hyperthyroidism in vivo on the status of the components of the fat-cell hormone-sensitive adenylate cyclase were investigated. The number of beta-adrenergic receptors was elevated by about 25% in membranes of fat-cells isolated from hyperthyroid rats as compared with euthyroid rats, but their affinity for radioligand was unchanged. Membranes of hyperthyroid-rat fat-cells displayed less than 65% of the normal complement of receptors for [3H]cyclohexyladenosine. The affinity of the receptors for this ligand was normal. In contrast with the marked increase in the amounts of the alpha-subunits of the guanine nucleotide-binding proteins Gi (Mr 41,000) and Go (Mr 39,000) observed in the hypothyroid state [Malbon, Rapiejko & Mangano (1985) J. Biol. Chem. 260, 2558-2564], the amounts of alpha-Gi, alpha-Go as well as alpha-Gs subunits [Mr 42,000 (major) and 46,000/48,000 (minor)] were not changed by hyperthyroidism. Adenylate cyclase activity in response to forskolin, guanosine 5'-[gamma-thio]triphosphate or isoprenaline, in contrast, was decreased by 30-50% in fat-cell membranes from hyperthyroid rats. Fat-cells isolated from hyperthyroid rats accumulated cyclic AMP to less than 50% of the extent in their euthyroid counterparts in the presence of adenosine deaminase and either adrenaline or forskolin, suggesting a decrease in the amount or activity of the catalytic subunit of adenylate cyclase. In the absence of exogenous adenosine deaminase, cyclic AMP accumulation in response to adrenaline was elevated rather than decreased in fat-cells from hyperthyroid rats. The inhibitory influence of adenosine is apparently limited in the hyperthyroid state by the decreased complement of inhibitory R-site purinergic receptors in these fat-cells. Short-term hyperthyroidism modulates the fat-cell adenylate cyclase system at the receptor level (beta-receptor number increased, R-site purinergic-receptor number decreased) and the catalytic subunit of adenylate cyclase.
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PMID:Short-term hyperthyroidism modulates adenosine receptors and catalytic activity of adenylate cyclase in adipocytes. 303 73

Adenosine and its synthetic analogues are known to affect many leukocyte functions, in some cases by binding to specific cell surface receptors coupled to adenylate cyclase. In this study, adenosine receptors were demonstrated on normal rabbit alveolar macrophages by examining specific binding of tritiated 5-N-ethylcarboxamide adenosine (NECA) to intact cells. Scatchard analysis suggested a single class of approximately 33,000 binding sites per cell and an estimated Kd of 0.46 mumol/L. Competitive inhibition of tritiated NECA binding was demonstrated for 2-chloroadenosine (2-CA; Ki = 3.68 mumol/L) and L-phenylisopropyl adenosine (L-PIA; Ki greater than 100 mumol/L), a rank order of binding affinities indicative of an A2 receptor. Theophylline and isobutyl methylxanthine had Kis of 368 and 27.6 mumol/L, respectively. For functional correlation, NECA was found to be 10-fold more potent than L-PIA in stimulating an increase in intracellular cyclic adenosine monophosphate. In addition, macrophages were cultured for 24 hours with NECA, 2-CA, or L-PIA to determine whether these analogues modulated expression of either cell-associated procoagulant activity or elaboration of plasminogen activator. Procoagulant activity was suppressed by as much as 62% (P less than 0.05); the rank order of potency and blockade of the effect with theophylline suggest that suppression of procoagulant activity occurred primarily by stimulation of A2 receptors. By contrast, these analogues stimulated production and release of plasminogen activator by 30% (P less than 0.05), but this effect had none of the features of an A2-mediated mechanism. Macrophages were cotreated with nitrobenzylthioinosine (10 mumol/L) and adenosine deaminase (2 U/ml) to allow adenosine accumulation exclusively within the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptors on rabbit alveolar macrophages: binding characteristics and effects on cellular function. 303 32


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