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Query: UNIPROT:P06889 (Mol)
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Adenosine receptors are present in platelets, and their activation results in accumulation of cAMP and inhibition of aggregation. The study of platelet adenosine receptors, however, is limited by the impossibility of maintaining these cells in vitro. Human erythroleukemia (HEL) cells express megakaryocytic/platelet markers and have been used as a model to study platelet receptors. Therefore, we sought to determine whether adenosine receptors were present in HEL cells. Adenosine agonists produced an accumulation of cAMP in HEL cells, implying the presence of A2 receptors. Xanthine and nonxanthine adenosine receptor antagonists blocked this effect in a simple competitive manner (Schild analysis). Therefore, both platelets and HEL cells possess A2 adenosine receptors. There were, however, significant differences between them. Adenosine agonists were, in general, less potent in HEL cells, compared with platelets. In particular, the adenosine analog CGS 21680, one of the most potent agonists in platelets, was virtually inactive in HEL cells. The orders of potencies for agonists (and their EC50 values for cAMP production) were 5'-N-ethylcarboxamidoadenosine (0.19 microM) = CGS 21680 (0.18 microM) > (R)-(-)-N6-(2-phenylisopropyl)adenosine (0.5 microM) in platelets and 5'-N-ethylcarboxamidoadenosine (2.4 microM) > (R)-(-)-N6-(2-phenylisopropyl)adenosine (160 microM) >> CGS 21680 (1600 microM) in HEL cells. In contrast to the decreased potency of agonists in HEL cells, the antagonist 1,3-dipropyl-8-p-sulfophenylxanthine was more potent in HEL cells, compared with platelets. Based on the striking differences in the rank orders of potencies of agonists and antagonists, we propose that HEL cells and platelets have different subtypes of adenosine A2 receptors. We found CGS 21680 particularly helpful in distinguishing between these receptor subtypes.
Mol Pharmacol 1993 Jun
PMID:Characterization of adenosine receptors in human erythroleukemia cells and platelets: further evidence for heterogeneity of adenosine A2 receptor subtypes. 839 Nov 17

Adenosine causes airway obstruction in asthmatics and smokers. Theophylline and cromolyn, drugs used to treat these patients, bind to human lung adenosine receptors (ARs). This study investigated whether A1ARs and/or A2ARs are functionally present in human lung and airways, and whether theophylline and/or cromolyn antagonize their function. Peripheral lung or airway fragments from 21 people were incubated for 15 min with (1) an A1AR agonist, N6-cyclopentyladenosine (CPA, 5 to 1,000 nM), or (2) an A2AR agonist, either 5'-N-ethylcarboxamido adenosine (NECA, 0.5 to 20 microM) or 2-[p-(2-carboxyethyl)-phenethyl amino]-5'-N-ethylcarboxamido adenosine (CGS 21680, 0.5 to 28 microM), in the presence of the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (50 nM) and/or (3) theophylline (1 mM) and/or (4) cromolyn (500 microM). Adenosine deaminase (2 U/ml) and the phosphodiesterase inhibitor Ro 20-1724 (2 mM) were present in all incubations. Cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. In peripheral lung, CPA did not change baseline or isoproterenol-stimulated cAMP content. However, both NECA (20 microM) and CGS 21680 (28 microM) significantly (P < 0.05) increased cAMP content 220 +/- 4% and 201 +/- 32%, respectively (mean +/- SEM). In airways, 20 microM NECA increased cAMP content 129 +/- 34%, and 28 microM CGS 21680 increased it 52 +/- 20% (both P < 0.05). In both peripheral lung and airway tissue, NECA-induced increase in cAMP was antagonized by theophylline (P < 0.05) but not cromolyn. The lungs of younger, nonsmokers had lower baseline cAMP content but did not respond differentially to A2AR stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Aug
PMID:Effect of adenosine receptor ligands on cAMP content in human airways and peripheral lung. 839 27

Modulation of neutrophil responses by adenosine may have an important role in limiting tissue injury during inflammation or ischemia-reperfusion. Mac-1 (CD11/CD18), a member of the leukocyte integrin family, participates in neutrophil adhesion to endothelium, in transendothelial migration, and in phagocytosis. Using monoclonal antibodies and flow cytometry, we investigated the effect of adenosine on the increase in plasma membrane expression of Mac-1 which occurs following stimulation of neutrophils with the chemotactic peptide N-formylmethionylleucylphenylalanine (FMLP). Adenosine and 5'N-ethylcarboxamido-adenosine, a potent A2 agonist, each produced a dose-dependent inhibition of as much as 50% of the increase in Mac-1 expression on neutrophils stimulated with FMLP, with an IC50 of approximately 1 nM. The effect of adenosine was blocked by 8-p-sulfophenyltheophylline, an adenosine-receptor antagonist, N6-cyclopentyl-adenosine, an A1-selective agonist, had no effect on FMLP-stimulated Mac-1 expression in the concentration range expected for its action on neutrophil adenosine receptors of the A1 type. We also found that dibutyryl cyclic adenosine monophosphate inhibited the upregulation of Mac-1, and that the effect of adenosine on Mac-1 expression was not reversed by colchicine or vinblastine. We conclude that adenosine acts via A2 receptors to inhibit the upregulation of Mac-1 expression of FMLP-stimulated neutrophils, and that A1 receptors are not involved. This effect of adenosine may help to limit Mac-1-dependent neutrophil exudation at sites of inflammation or ischemia-reperfusion.
Am J Respir Cell Mol Biol 1993 Aug
PMID:Acting via A2 receptors, adenosine inhibits the upregulation of Mac-1 (Cd11b/CD18) expression on FMLP-stimulated neutrophils. 839 28

Pyrophosphate and 1-pyrophospho-5-phosphoribose displace the nucleotide from the complex with RecA protein (in the absence of DNA). Adenosine, AMP, inorganic phosphate riboso-5-phosphate have no effect. Pyrophosphate causes the dissociation of RecA-ssDNA-complex in the same manner as ADP, circular hexaphosphate has no effect. In the complex with RecA protein the dissociation constant for pyrophosphate is 1.6 mM and 710 mM for adenosine. It is proposed that the oligophosphate is the main binding group in the RecA-nucleotide interaction. Two vicinal "closed" -O and one terminal "open" oxygenous =O-groups of oligophosphate take part in the binding. The nucleoside fragment alone cannot provide the firm binding of the nucleotide with the protein, but probably is responsible for the specificity of the nucleotide to protein binding.
Mol Biol (Mosk)
PMID:[The role of oligophosphate and nucleoside fragments upon the interaction of a nucleotide with RecA protein]. 848 59

This study was aimed to determine whether singlet oxygen (1O2) attenuates 5'-nucleotidase activity in the ischemic myocardium. Isolated rat hearts were exposed to either exogenous 1O2 produced by irradiating rose bengal or 40-min ischemia and reperfusion. Ecto-5'-nucleotidase activity was inhibited by exogenous 1O2 (3.74 +/- 0.38 mumol/min/g dry weight), when compared with normal control (7.52 +/- 0.41 mumol/min/g dry weight; P < 0.05). The enzymatic activity was significantly preserved by histidine (25 mM)--a 1O2 scavenger (7.04 +/- 0.61 mumol/min/g dry weight; P < 0.05 v rose bengal group). After ischemia, the activity of ecto-5'-nucleotidase was greatly reduced (2.51 +/- 0.25 mumol/min/g dry weight), when compared with normal control. Histidine significantly enhanced ecto-5'-nucleotidase activity (6.55 +/- 0.52 mumol/min/g dry weight, P < 0.05 v ischemic control). Adenosine release was consistent with ecto-5'-nucleotidase activity. The time course studies of effects of 1O2 on coronary flow, cardiac function, and LDH release revealed that the damage by 1O2 to ecto-5'-nucleotidase activity and adenosine release primarily accounted for impaired coronary flow, cardiac dysfunction, and impaired cardiac metabolism. Lipid peroxidation induced by exogenous 1O2 or ischemia was in parallel with ecto-5'-nucleotidase deactivation by 1O2. It is concluded that 1O2 causes inactivation of ecto-5'-nucleotidase and attenuation of adenosine release which could possibly be one of the important mechanisms of oxygen radical-mediated myocardial injury.
J Mol Cell Cardiol 1995 Nov
PMID:Interaction of singlet oxygen with 5'-nucleotidase in rat hearts. 859 96

Adenosine is one of the most important inhibitory modulators of heart function, producing negative inotropic, chronotropic and dromotropic effects and is also a major regulator of coronary circulation. The decrease in contractility by adenosine is mediated through inhibition of adenylyl cyclase by Gi-proteins coupled to adenosine receptors. However, little is known about the developmental differences in the effect of adenosine on cardiac cells. We have now shown that there is a striking developmental difference in the inhibitory effect of adenosine on isoproterenol-stimulated ICa between adult and newborn rabbit ventricular cells. Adenosine had no significant inhibitory effect on 0.1 muM isoproterenol-stimulated ICa in adult cells, while it completely blocked the 10 muM isoproterenol-stimulated ICa in newborn cells with an inhibitory potency similar to carbachol in newborn cells. Similarly, adenosine did not decrease the isoproterenol-stimulated cAMP levels in adult cells while it inhibited isoproterenol-stimulated cAMP levels significantly and equipotently to carbachol in newborn. However, for forskolin-stimulated ICa and cAMP levels in newborn cells, adenosine had a much lower inhibitory potency than carbachol. In adult cells, forskolin-stimulated ICa and cAMP levels were not affected by adenosine. We showed previously that the Gia3 isoform of inhibitory G protein was present in newborn cell membranes, but not detectable in adult cell membranes. We have now used a synthetic decapeptide corresponding to the C-terminal sequence of Gia3 in the patch pipette and have shown a selective partial block of the inhibitory action of adenosine for isoproterenol-stimulated ICa, suggesting that the inhibitory action of adenosine on ICa is mediated primarily through the Gia3 pathway.
J Mol Cell Cardiol 1996 Feb
PMID:Adenosine and carbachol are not equivalent in their effects on L-type calcium current in rabbit ventricular cells. 872 71

Hyperkalemic cardioplegic solutions produce cardiac arrest during open heart surgery by depolarizing the sarcolemma. A recognized adverse effect of hyperkalemic cardioplegia is the possible development of ventricular dysfunction believed to be related to intracellular Ca2+ loading, a consequence of K(+)-induced membrane depolarization. Adenosine has been proposed as an adjunct to hyperkalemic cardioplegic solutions. However, it is not known whether adenosine can affect K(+)-induced membrane depolarization, and associated intracellular Ca2+ loading. Perforated patch-clamp method, applied to isolated single guinea-pig ventricular myocytes, revealed that adenosine (1 mM) did not significantly reduce the magnitude of K(+)-induced membrane depolarization (35.7 +/- 1.7 v 31.0 +/- 1.1 mV in the absence v presence of adenosine). Yet, adenosine significantly slowed the rate of K(+)-induced membrane depolarization (167 +/- 32.8 v 67.9 +/- 12.9 mV/min in the absence v presence of adenosine) without directly affecting Ca2+, Na+, and K+ currents. Imposed ramp-pulses, with different rates (ranging from 0.33 to 0.05 V/s), but same magnitude of depolarization (100 mV), demonstrated that reduction in the rate of membrane depolarization decreases net inward Ca2+ current. Indeed, in Fluo-3 loaded ventricular myocytes, imaged by laser confocal microscopy, adenosine (1 mM) prevented K(+)-induced intracellular Ca2+ loading. The present findings indicate that adenosine slows the rate of K(+)-induced membrane depolarization, and reduces K(+)-induced intracellular Ca2+ loading in ventricular myocytes. Such findings support the notion that adenosine may play a cardioprotective role in hyperkalemic cardioplegia.
J Mol Cell Cardiol 1996 Jun
PMID:Adenosine slows the rate of K(+)-induced membrane depolarization in ventricular cardiomyocytes: possible implication in hyperkalemic cardioplegia. 878 61

Although adenosine receptors have been implicated in the induction of preconditioning in a variety of experimental models, there is controversy concerning the specific adenosine receptor subtypes mediating this effect. Concentration-protection relationships for adenosine and adenosine agonists in rabbit cardiomyocytes were used to characterize the role of adenosine receptor subtypes in preconditioning. Isolated cells were ischemically preconditioned or pre-incubated for 10 min with increasing concentrations of adenosine, CCPA (2-chloro-N6-cyclopentyladenosine), APNEA (N6-2-(4-aminophenyl)ethyladenosine), or BNECA (N6-benzyl-5'-N-ethyl-carboxamidoadenosine) in the presence or absence of 1 or 10 microM of the selective A1-adenosine antagonist DPCPX (8-Cyclopentyl-1,3-dipropylxanthine). Following a 30-min post-incubation period, cells were pelleted, layered with oil and ischemically incubated for 180 min. Injury was assessed by osmotic swelling and trypan blue exclusion of sequential samples, and determination of the areas beneath the mortality curves. Adenosine produced a broad concentration-protection curve which was displaced to the right by DPCPX. The curve for A1-selective agonist CCPA was biphasic, with an initial response below 1 nM and a second above 1 microM. DPCPX abolished the early response leaving a steep monophasic curve between 0.1 and 10 microM CCPA. The APNEA curve appeared moriophasic, the major slope occurring between 1-100 nM; DPCPX (1 microM) shifted the concentration-response curve approximately 30-fold and decreased the slope. Adenosine receptor agonist BNECA produced preconditioning characterized by a shallow monophasic concentration-protection curve with a maximal effect of 49% and an EC50 of approximately 5 nM; DPCPX shifted the BNECA concentration-protection relationship approximately 40-fold with only a modest increase in slope. Analysis of the data suggests that induction of preconditioning results from interaction of agonists with the A1 receptor and a second adenosine receptor having properties consistent with the A3 receptor. Adenosine, CCPA, APNEA, BNECA and DPCPX each appear to be selective for the A1 adenosine receptor subtype in isolated rabbit cardiomyocytes.
J Mol Cell Cardiol 1996 Jun
PMID:Concentration-response relationships for adenosine agonists during preconditioning of rabbit cardiomyocytes. 878 77

The rat A2a adenosine receptor, a G protein-coupled receptor, was functionally expressed in the yeast Saccharomyces cerevisiae. High affinity binding sites for A2a adenosine agonists were detected in yeast membranes containing the endogenous Grx protein Gpa1. Agonist saturation binding isotherms using [3H]5'-N-ethylcarboxamidoadenosine indicated that the A2a adenosine receptor expressed in yeast cell membranes displays pharmacological properties equivalent to those observed when the receptor is expressed in human embryonic kidney 293 cell membranes. The rank order of potency of various agonists in [3H]5'-N-ethylcarboxamidoadenosine competition binding assays performed with yeast cell membranes was comparable to that seen for the receptor expressed in mammalian cell membranes. Adenosine agonist-dependent growth response of yeast strains expressing the A2a adenosine receptor was elicited via activation of the yeast pheromone-response pathway. Induction of a pheromone-responsive FUS1-HIS3 reporter gene in far1 his3 cells permits cell growth in medium lacking histidine. The sensitivity of the bioassay was increased by deletion of the STE2 gene, which encodes the yeast alpha-mating pheromone receptor. The growth response was dose dependent, and agonists of varying affinities displayed a rank order of potency comparable to that observed in competition binding assays. Agonist-activated growth assays performed in liquid culture gave ED50 values for various adenosine agonists consistent with reported Kd alpha values. Yeast strains expressing a single receptor/G protein complex will be useful as a model system for the study of receptor/G protein interactions in vivo.
Mol Pharmacol 1996 Oct
PMID:Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway. 886 27

Adenosine, synthesized by ecto-5'-nucleotidase, is cardioprotective against ischemia and reperfusion injury. We have previously reported that activation of protein kinase C increases ecto-5'-nucleotidase activity of the rat cardiomyocytes, raising the possibility that activation of protein kinase C protects cardiomyocytes from the irreversible cellular injury via activation of ecto-5'-nucleotidase. To test this hypothesis, cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode buffer solution. The cardiomyocytes were incubated with and without exposure to methoxamine (1 x 10(-6) mol/l) or phorbol 12-myristate 13-acetate (PMA. 1 x 10(-8) mol/l). Ecto-5'-nucleotidase activity increased 15 min after the onset of an exposure to either methoxamine or PMA. Adenosine release during hypoxia and reperfusion was augmented in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated cardiomyocytes, which was inhibited by alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase. Irreversible cellular injury assessed by the extent of release of lactate dehydrogenase and the trypan blue exclusion test following 60 min of hypoxia and 60 min of reoxygenation was attenuated in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated group, which was also blunted by AOPCP and 8-sulfophenyltheophylline, an adenosine receptor antagonist. An adenosine A1 receptor agonist, N6-cyclohexyladenosine, restored the cardioprotection under the treatment with PMA and AOPCP. We conclude that activation of ecto-5'-nucleotidase via protein kinase C contributes to the attenuation of the irreversible injury of the rat cardiomyocytes due to hypoxia and reoxygenation.
J Mol Cell Cardiol 1996 Sep
PMID:Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes. 889 53


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