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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cDNA of an unidentified recently cloned G protein-coupled receptor, RDC8, has been expressed in Y1 adrenal cells, in dog thyrocytes in primary culture and in Xenopus oocytes. In all these systems this resulted in the activation of adenylyl cyclase and of the cyclic AMP cascade in the absence of any added external signal. However, this physiologically constitutive activator was inhibited by adenosine deaminase and by inhibitors of the adenosine A2 receptor. Cos 7 cells transfected with RDC8 cDNA constructs acquired binding characteristics of an adenosine A2 receptor. Moreover, RDC8 mRNA and adenosine A2 receptors display a very similar distribution in the brain. RDC8 therefore codes for an A2 adenosine receptor. Whether the physiologically constitutive activation of this receptor is entirely explained by endogeneously produced adenosine is as yet unknown.
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PMID:RDC8 codes for an adenosine A2 receptor with physiological constitutive activity. 212 16

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

This study 1) compares the negative chronotropic and dromotropic actions of adenosine in guinea pig, rat, and rabbit hearts; 2) investigates the mechanism(s) for the different responses; and 3) determines the physiological implications. Isolated perfused hearts were instrumented for measurement of atrial rate and atrioventricular (AV) nodal conduction time. Differences in metabolism of adenosine were determined in the absence and presence of dipyridamole (nucleoside uptake blocker) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, adenosine deaminase inhibitor). Dipyridamole plus EHNA decreased adenosine's EC50 for the negative dromotropic effect by 14-fold in guinea pig heart and 1.6-fold in rat heart. This is consistent with the greater number of [3H]nitrobenzylthioinosine binding sites measured in membranes from guinea pig (1,231 +/- 68 fmol/mg protein) compared with rat (302 +/- 31 fmol/mg protein) and rabbit (260 +/- 28 fmol/mg protein) atria. The potency of adenosine to slow atrial rate and prolong AV nodal conduction time was greater in guinea pig than in rat or rabbit hearts. This rank order of potency correlated well with the number of binding sites for the specific adenosine receptor radioligand 125I-aminobenzyladenosine in guinea pig (102 +/- 13 fmol/mg protein), rat (11 +/- 0.5 fmol/mg protein), and rabbit (8 +/- 1 fmol/mg protein) atrial membranes. Hypoxia increased the rate of adenosine release by severalfold and caused slowing of heart rate and AV block. In spontaneously beating hearts, the main effect of hypoxia was a slowing of ventricular rate, which in the guinea pig heart was due to AV block and in the rat heart to atrial slowing. In atrial paced hearts, hypoxia caused a marked prolongation of AV nodal conduction time in guinea pig (39 +/- 4 msec) and rabbit (29 +/- 5 msec) hearts, but only small effect in rat hearts (10 +/- 2 msec). The differences in response to hypoxia could be accounted for by the species-dependent differences in the 1) amount of adenosine released and metabolized, 2) sensitivity of the hearts to adenosine, and 3) dependency of AV nodal conduction on atrial rate. The findings indicate that the results from physiological or pharmacological studies on adenosine in one species may not be applicable to others, and the ultimate effect of adenosine and hypoxia is to slow ventricular rate.
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PMID:Species-dependent effects of adenosine on heart rate and atrioventricular nodal conduction. Mechanism and physiological implications. 220 18

A new radiolabeled adenosine receptor agonist, 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadeno sin e (CGS 21680), apparently specific for high-affinity binding sites of the A2 subtype in rat brain, was used to identify and pharmacologically characterize adenosine receptors in human brain. The binding of [3H]CGS 21680, as determined by standard radioligand binding technique in the presence of exogenously added adenosine deaminase, reached equilibrium after 40 min at 25 degrees C. In saturation studies, a single class of high-affinity binding sites with values for KD of 22 +/- 0.5 nM and Bmax of 444 +/- 63 fmol/mg of protein were observed. Similar binding characteristics were observed regardless of whether rapid filtration or centrifugation was used to separate bound versus free ligand. Of the 14 brain regions examined, [3H]CGS 21680 binding was highest in putamen, followed by globus pallidus and caudate nucleus. The level of [3H]CGS 21680 binding in these areas of basal ganglia was identical to 5'-N-[3H]ethylcarboxamidoadenosine ([3H]NECA) binding in the presence of 50 nM N6-cyclopentyladenosine (CPA). The rank order of agonist potencies as determined by a series of competition experiments was NECA greater than or equal to CGS 21680 greater than 2-chloroadenosine greater than N6-(R)-phenylisopropyladenosine greater than N6-cyclohexyladenosine greater than N6-(S)-phenylisopropyladenosine. This potency order was the same for the binding of [3H]CGS 21680 to rat, and of [3H]NECA in the presence of 50 nM CPA to rat and human, brain membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of the adenosine A2 receptor ligand [3H]CGS 21680 to human and rat brain: evidence for multiple affinity sites. 221 23

Adenosine has been shown in vitro to be a potent antilipolytic agent and an inhibitor of insulin-stimulated glucose utilization in skeletal muscle. To test whether endogenously produced adenosine (e.g., from ATP hydrolysis) shares these deleterious effects on substrate mobilization and utilization and thus limits maximum thermogenesis in vivo, adenosine deaminase (converts adenosine to inosine) was given to rats 15 min before cold exposure. Significant (P less than 0.05) increases in thermogenesis were observed under both well-fed (100 units/kg ip) and food-rationed (200 units/kg ip) states. Significant (P less than 0.05) increases in thermogenesis and cold resistance were also observed after pretreatment with selective adenosine receptor antagonists [8-cyclopentyltheophylline (1 microgram/kg ip) greater than 1,3-dipropyl-8-p-sulfophenylxanthine (1.25 mg/kg ip) greater than aminophylline (18.7 mg/kg ip)], indicating an A1-receptor-mediated effect. These results indicate that endogenously released adenosine can indeed attenuate the thermogenic capacity in severe cold and that adenosine antagonists, especially those selective for A1-receptor, are useful in improving cold resistance under varying nutritional states.
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PMID:Enhancement of maximal thermogenesis by reducing endogenous adenosine activity in the rat. 231 70

Previously we have shown that systemic injection of adenosine antagonists can significantly improve cold tolerance in both rats and humans. However, it is not clear whether systemic administration of adenosine antagonist acts peripherally or centrally at the thermoregulatory site. To resolve this, theophylline (nonselective adenosine receptor blocker), cyclopentyltheophylline (selective A1 receptor blocker) or adenosine deaminase (an enzyme which inactivates adenosine by converting it into inosine) was injected directly into preoptic anterior hypothalamus (POAH) of rats and their thermogenic responses assessed. In contrast to that observed after systemic administration, intrahypothalamic injection of either adenosine antagonists or deaminase at various doses failed to elicit any enhancement in heat production beyond that of the controls. These results suggest that the beneficial effect of systemically injected adenosine antagonists in improving cold tolerance is not the result of altering the thermoregulatory functions mediated via the POAH.
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PMID:Do adenosine antagonists improve cold tolerance by reducing hypothalamic adenosine activity in rats? 233 20

Chlorotetracycline has been used in human polymorphonuclear leukocytes as a probe to investigate the state of membrane-bound calcium. We examined the effect of adenosine on the fluorescence responses of CTC-loaded PMNs stimulated with the synthetic chemotactic peptide, formyl-methionyl-leucyl- phenylalanine. Adenosine inhibited the decrease in CTC fluorescence in a dose-dependent fashion and its effect was reversed by theophylline, an adenosine receptor antagonist. Removal of extracellular adenosine by incubating PMNs with adenosine deaminase abolished the effect of adenosine. These data suggest that adenosine inhibits the release of membrane-bound calcium in PMNs that normally occurs in response to chemotactic stimuli, acting via PMN surface adenosine receptors.
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PMID:The effect of adenosine on the fluorescence responses of chlorotetracycline-loaded human polymorphonuclear leukocytes. 238 62

In summary, this study characterized the biphasic inhibition of fat cell glucose transport by the lipolytic agents caffeine and theophylline. Like the lipolytic drug forskolin, both methylxanthines produced an immediate inhibition of glucose transport that was not seen with 8-phenyltheophylline, a pure adenosine receptor antagonist. The immediate inhibition was therefore not mediated by the adenosine receptor antagonism but seems to be due to a direct interaction with the hexose transporter. This conclusion is supported by the immediate onset of the inhibition and additionally by the interference of theophylline and caffeine with the binding of cytochalasin B, a ligand of the glucose transporter that binds to an intracellular site of the transporter molecule. In addition, a second, delayed inhibitory effect of theophylline and caffeine on glucose transport was observed. This portion shared many aspects of the inhibitory effect of lipolytic hormones. It developed over a period of about 5 min and was antagonized by the simultaneous addition of the antilipolytic hormone PGE2. This component of transport inhibition could be attributed to the antagonistic effect of methylxanthines at the fat cell A1-adenosine receptor since it was also seen with 8-phenyltheophylline. This conclusion is further supported by data showing that the removal of endogenous adenosine with adenosine deaminase resulted in a comparable 25-30% inhibition of insulin-stimulated glucose transport. In addition, the time course of glucose transport inhibition by the subsequent addition of adenosine deaminase is similar to that of the delayed portion of the inhibition seen with theophylline and caffeine. Both treatments produced their maximal inhibition after 5 min. In conclusion, the methylxanthines theophylline and caffeine inhibit glucose transport by a combination of two different modes of action. The immediate major component is mediated via a direct interaction with the hexose transporter whereas the delayed component involves adenosine receptor antagonism and thereby the interaction with G-proteins.
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PMID:Methylxanthines inhibit glucose transport in rat adipocytes by two independent mechanisms. 239 Jan 12

To determine the mechanism(s) of transcellular adenosine transport in epithelial tissues that possess an adenosine receptor response, we studied [3H]adenosine uptake using vesicles prepared from isolated brush-border and basolateral membranes of the rabbit ileum. In the presence of the adenosine deaminase inhibitor deoxycoformycin uptake of [3H]adenosine into brush-border membrane vesicles is stimulated fivefold by an inwardly directed Na gradient. Na-dependent [3H]adenosine uptake is enhanced and concentrative under conditions that increase inside negativity of vesicles, thus providing evidence for an electrogenic carrier. Na-dependent adenosine uptake is a saturable function of adenosine concentration with a Michaelis-Menten constant of 17.3 +/- 7.1 microM and maximum transport rate of 216.9 +/- 20.2 pmol.min-1.mg protein-1. Both uridine and inosine inhibit [3H]adenosine uptake, suggesting that the Na-dependent transporter has broad substrate specificity for both purine and pyrimidine ribonucleosides. Na-dependent adenosine uptake is inhibited by dipyridamole but is insensitive to 6-(4-nitrobenzyl)thio-9-beta-D-ribofuranosylpurine. We conclude that adenosine is transported across ileal brush-border membranes by a Na-ribonucleoside cotransport system. In contrast, adenosine uptake in basolateral membranes is not stimulated by a Na gradient. These studies show asymmetry in the distribution of transport systems for adenosine in polarized intestinal epithelia.
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PMID:Sodium-adenosine cotransport in brush-border membranes from rabbit ileum. 239 91

The purpose of this study was to test the hypothesis that endogenous adenosine functions to restrain the renin release response to pharmacological and pathophysiological stimuli. To achieve this objective, we examined the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX), on the renin release response induced by acute administration of hydralazine or by chronic clipping of the left renal artery (renovascular hypertensive rats). In conscious, unrestrained rats, DPSPX significantly increased plasma renin activity (PRA) in control rats, in rats treated with hydralazine, and in renovascular hypertensive rats. The effect of DPSPX on PRA was significantly greater in rats treated with hydralazine or in renovascular hypertensive rats compared with control rats. DPSPX did not influence arterial blood pressure in any group, did not affect the measurement of PRA, and did not alter the elimination of renin activity from the circulation. Additional experiments were performed in the in situ autoperfused kidney so that the effects of DPSPX on renal hemodynamics and renal excretory function could be assessed. In this experimental model, DPSPX also increased PRA in hydralazine-treated rats and in renovascular hypertensive rats without affecting arterial pressure, renal blood flow, or sodium excretion. In a final set of studies in conscious, unrestrained rats, adenosine deaminase increased PRA in a dose-dependent manner in hydralazine-treated rats and significantly increased the slope of the relation between PRA and the depressor response to hydralazine. We conclude: 1) Although the kidney has both A1 and A2 adenosine receptors mediating inhibitory and stimulatory actions, respectively, on renin release, the dominant effect of endogenous adenosine on renin release is inhibitory. 2) Even under basal physiological conditions, endogenous adenosine tonically inhibits renin release. 3) This inhibitory effect is augmented whenever the renin-angiotensin system is stimulated regardless of the approach used to activate renin release. 4) Endogenous adenosine negatively modulates renin release by a direct effect on juxtaglomerular cells.
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PMID:Endogenous adenosine restrains renin release in conscious rats. 240 69


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