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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because adenosine narrows asthmatic airways, is released during hypoxia and by mast cells, and is antagonized by theophylline, it may play a role in asthma. I characterized the first step in pulmonary responses to adenosine: its adenosine receptor. Plasma membranes, prepared from macroscopically normal human peripheral lung, were incubated with 10 nM 5'-N-ethylcarboxamido[3H]adenosine ([3H]NECA) and various concentrations of competing ligand under experimentally determined optimal conditions: 4 degrees C, pH 7.4, 5 mM MgCl2, 1.8 mg protein/ml, 30-min incubation time. Bound and free ligand were separated by rapid vacuum filtration, and the radioactive counts were analyzed using a weighted, non-linear, least-squares curve-fitting program, LIGAND. Analyzed together, the data from the lungs of 6 patients revealed a single binding site with a dissociation constant (Kd) for NECA of 200 nM +/- 14% and a receptor concentration of 543 fmol/mg protein +/- 13%. Analyzed separately, the individual Kds ranged from 133 to 430 nM and the receptor concentrations from 338 to 811 fmol/mg protein. Adenosine receptor ligands competed with NECA in an A2 rank order of potency: NECA greater than 8-phenyltheophylline greater than 3-isobutyl-1-methylxanthine greater than theophylline greater than N6-L-phenylisopropyladenosine greater than N6-D-phenylisopropyladenosine greater than N6-cyclohexyladenosine. Theophylline bound to the receptor with an inhibition constant (Ki = 70.9 microM +/- 28%) near the therapeutic range (28 to 56 microM). Cromolyn also bound with high affinity (Ki = 5.42 microM +/- 47%). I conclude that human lung adenosine receptors: (1) are single-site receptors, probably of the A2 subtype and (2) bind to both theophylline and cromolyn.
Am J Respir Cell Mol Biol 1990 Feb
PMID:Characterization of the human peripheral lung adenosine receptor. 240 76

Adenosine stimulates and inhibits adenylate cyclase activity and cAMP levels in WI-38 and VA13 fibroblasts. The inhibitory effects appear to be mediated by both A1 receptors and the P-site. Results supporting these conclusions are as follows: Adenosine by itself increased cAMP accumulation in these cells. PGE1-stimulated cAMP accumulation was inhibited by adenosine in a concentration-dependent fashion. IAP treatment blocked adenosine inhibition of cAMP accumulation and adenylate cyclase activity and enhanced adenosine stimulation of cAMP accumulation in VA13 cells. Theophylline and MIX attenuated adenosine inhibition of cAMP accumulation. Adenosine analogs with substitutions in the purine ring inhibited PGE1-stimulated cAMP accumulation and adenylate cyclase activity. PGE1-stimulated cAMP accumulation was inhibited by the P-site agonist 2'5'-dideoxyadenosine, but this inhibition was not attenuated by MIX or IAP treatment. These data support the idea that adenosine may inhibit cAMP accumulation in VA13 or WI-38 cells by acting at an A1 receptor of the P-site. The decrease in cAMP accumulation mediated by the A1 receptor appeared to be due at least in part to an Ni-mediated inhibition of adenylate cyclase.
Mol Cell Endocrinol 1986 Mar
PMID:A1 and A2 adenosine receptors regulate adenylate cyclase in cultured human lung fibroblasts. 242 Jun 58

Surface binding of anti-actin IgG alone or in a Mr = 716 000 [(IgG)2 Protein A]2 complex results in a stimulation of DNA synthesis and cell growth in L cells. Cyclic-AMP (0.01-1.0 mM) added to such cell cultures augmented DNA synthesis as measured by incorporation of [3H]thymidine into DNA. Theophylline (0.1-1.0 mM), a phosphodiesterase inhibitor which prevents enzymatic breakdown of cAMP, had similar effects, but cGMP (0.01-1.0 microM) reversed the effects of cAMP and theophylline upon DNA synthesis. Analysis of the cell cycle by flow cytometry revealed that antibody produced a shift (7%) of cells from the G1-phase to the S-phase (DNA-synthetic) of the cell cycle at 72 hr of incubation. Addition of cAMP (0.5 mM) to cell cultures, however, produced significant shifts of antibody stimulated cells from G1-phase to S-phase at all time points measured, i.e., 24 (12%), 48 (22%), 72 hr (23%). Thus, antibody recruited cells into S-phase of the cell cycle and cAMP greatly augmented the effect. These observations suggest that the mechanism of activation of L cell growth by antibody to surface antigens involves a recruitment of cells into the DNA-synthetic phase and that the effect may be mediated by cAMP.
Mol Cell Biochem 1985 Jul
PMID:Cyclic AMP and theophylline enhance DNA synthesis in L cells stimulated with anti-actin IgG and [(IgG)2 protein A]2 complex by recruiting cells into S-phase. 299 89

Epimastigote forms of Trypanosoma cruzi contain a soluble cAMP phosphodiesterase. Optimal activity was found at pH 8.0 and in the presence of 5 mM Mn2+. Other cations were less efficient and did not give rise to an additional stimulation when added in the presence of optimal concentrations of Mn2+. The enzyme is not Ca2+ dependent. The apparent Km of the enzyme for the substrate is 40 microM and no kinetic evidence for the existence of two enzymes has been found. Theophylline and caffein did not inhibit the T. cruzi cAMP phosphodiesterase. The enzyme activity does not change during cell growth suggesting that the fluctuation observed in the levels of cAMP are largely a response to variations in adenylyl cyclase activity. The intracellular concentrations of cAMP ranged between 0.04--0.15 microM. No evidence that the T. cruzi cAMP phosphodiesterase is regulated by an endogenous activator could be found. However, T. cruzi contains a heat-stable, low molecular weight, non-dialysable protein that activates mammalian cAMP phosphodiesterase in the presence of Ca2+. The properties so far studied of such an activator suggest that it might be equivalent to other Ca2+-dependent regulators described in vertebrate and invertebrate species.
Mol Biochem Parasitol 1980 Apr
PMID:cAMP phosphodiesterase and activator protein of mammalian cAMP phosphodiesterase from Trypanosoma cruzi. 625 27

The effects of theophylline on insulin receptors and insulin action in isolated rat adipocytes were studied. Theophylline reduced insulin binding by a decrease of receptor affinity. As concentration-response curves revealed, the effect was paralleled by a reduction of the cellular ATP content. Basal as well as insulin-stimulated glucose transport (2-deoxyglucose and 3-O-methylglucose uptake) were inhibited by much smaller theophylline concentrations (0.15-0.6 mM) than those necessary to reduce insulin binding and to lower ATP levels (1-4.8 mM), or to stimulate lipolysis (0.3-2.4 mM). Insulin fully antagonized the effect of theophylline on lipolysis but failed to reverse the inhibition of glucose transport completely. The results suggest that (a) theophylline impairs insulin action at a post-receptor level and, at higher concentrations, by a decrease of receptor binding, (b) the reduction of insulin receptor affinity probably reflects ATP depletion of the adipocyte, and (c) the xanthine inhibits glucose transport independently from its effects on lipolysis.
Mol Cell Biochem 1983
PMID:Effects of theophylline on insulin receptors and insulin action in the adipocyte. 636 17

We examined the effects of extracellular ATP on the proliferation and synthesis of DNA by guinea pig alveolar macrophages (AM). AM proliferated spontaneously in vitro, their number doubling in 72 h. Such proliferation was completely inhibited by adding 1 mM ATP to the culture. The inhibition was dose dependent. ATP also suppressed the spontaneous synthesis of DNA by AM. The inhibitory effect of ATP was not related to cell damage, as the viability and the superoxide anion-generating activity of these cells were unaffected by treatment with ATP for 24 h. The order of potency of the adenosine nucleotides (ATP > ADP > AMP) reflected the character of the P2 purinoceptor. Theophylline inhibited the effect of ATP on the synthesis of DNA by AM to a level produced by the nonhydrolyzable analogue, ATP gamma S, but did not influence the effect of ATP gamma S. These data suggest that the effect of ATP on the synthesis of DNA was exerted mainly via the P2 purinoceptor (82.0%) and to a lesser extent via the P1 purinoceptor (12.6%). We found that small molecules in the lavage fluid inhibited the synthesis of DNA by AM. Thus, the extracellular ATP present in the alveolar lining fluid may participate in controlling the proliferation of AM.
Am J Respir Cell Mol Biol 1994 May
PMID:Extracellular ATP regulates the proliferation of alveolar macrophages. 817 20

Experiments were carried out to investigate the changes in intracellular Ca2+ transients associated with biphasic contractions that were elicited during interaction of theophylline with isoproterenol in the dog ventricular myocardium. For this purpose, effects of theophylline and isoproterenol on aequorin light transients and isometric contractions were assessed in the isolated canine ventricular trabeculae, superficial cells of which had been microinjected with the Ca2+ sensitive bioluminescent protein aequorin. The positive inotropic effect of theophylline (0.1-0.3 mM) was consistently associated with an increase in the amplitude of aequorin light transients. Theophylline at concentrations of 0.6 mM and higher decreased the amplitude of aequorin light transients, but the force of contraction increased further in association with a prominent prolongation of time to peak force. Theophylline (0.3 mM) enhanced the forskolin-induced increase in aequorin light transients and force. Theophylline (2 mM) inhibited the isoproterenol-induced increase in aequorin light transients associated with early phase of contraction in a reversible manner. A late phase of aequorin light transients was induced in association with late phase of contraction in the presence of both isoproterenol and theophylline. Thus, both the early and late phase of contraction were accompanied by corresponding phases of aequorin light transients. The relation between the amplitude of force and Ca2+ transients was markedly different and the late phase of contraction was associated with much lower aequorin light transients. The late phase of aequorin light transients induced by theophylline at a high concentration (10 mM) was enhanced by isoproterenol. These results indicate that theophylline (0.1-0.3 mM) increases the amplitude of Ca2+ transients through an accumulation of cyclic AMP by inhibition of the cyclic AMP phosphodiesterase activity. In concentrations of 0.6 mM and higher theophylline decreases the amplitude of the early phase aequorin light transients probably by inhibition of release of Ca2+ from the sarcoplasmic reticulum and induces simultaneously the late phase of contraction that may be associated with an increase in responsiveness to Ca2+ of myofibrils.
J Mol Cell Cardiol 1994 Jan
PMID:The effects of theophylline on aequorin light transients and force in the isolated dog right ventricular myocardium. 819 72

Theophylline, as used for the treatment of asthma and chronic obstructive pulmonary disease, may have several effects, including direct bronchodilation, improvement in diaphragmatic and ciliary function, and possibly immune modulation. In this study, we quantified the capacity for theophylline to inhibit natural killer (NK) cells and investigated the mechanism(s) that mediate this inhibition. Theophylline at 10 micrograms/ml and 20 micrograms/ml inhibited the tumoricidal activity of isolated peripheral blood lymphocytes (PBL) by 19 +/- 5% and 36 +/- 6%, respectively (n = 6). Using fluorescence-activated cell sorting, we purified NK cells from PBL and tested theophylline's effects on the kinetics of tumor lysis (Vmax) and on tumor binding. Theophylline at 20 micrograms/ml reduced Vmax by 40 +/- 9% but had no effect on tumor binding. We compared the effects of theophylline, which is both a phosphodiesterase (PDE) inhibitor and an adenosine receptor (AdR) antagonist, with agents that range from relatively pure AdR antagonists to pure PDE inhibitors. Inhibition of NK activity occurred only with PDE inhibitors. We also extracted lymphocyte PDE and observed a direct correlation (r2 = 0.99) between theophylline's activity as a PDE inhibitor and its capacity to inhibit NK activity. These results suggest that theophylline inhibits NK cytotoxicity through its activity as a PDE inhibitor. The clinical relevance of these findings awaits further study.
Am J Respir Cell Mol Biol 1993 Dec
PMID:Inhibition of natural killer cell activity by therapeutic levels of theophylline. 825 97

In this study the effects of 2',5'-dideoxyadenosine (DDA), an agonist of the intracellular adenosine binding site (P-site), on myocardial contractility, coronary resistance and cAMP-metabolism in the isolated guinea-pig heart were compared with those of adenosine. DDA (20-150 microM), like adenosine, dose dependently and reversibly inhibited the positive inotropic and chronotropic effect of beta-adrenergic stimulation with isoproterenol (8-54 pmol) up to 70% and 50%, respectively. In contrast to the known vasodilatory action of adenosine, however, basal coronary resistance remained unchanged with DDA. The antiadrenergic action of DDA was parallelled by changes in cAMP release from heart: stimulation with isoproterenol (16 pmol) increased cAMP release from 1.5 +/- 0.14 pmol cAMP/min under basal conditions to 5.2 +/- 0.45 pmol/min (mean +/- SE; n = 4). This increase was inhibited by 49% in presence of DDA (90 microM). Theophylline (50 microM), a well known antagonist of extracellular adenosine receptors, did not alter the potency of DDA. Our findings demonstrate, that DDA does not alter basal coronary flow but exerts a potent antiadrenergic action in heart which is P-site mediated.
J Mol Cell Cardiol 1993 Mar
PMID:Isoproterenol antagonistic effect of 2',5'-dideoxyadenosine in the isolated perfused guinea-pig heart. 838 89

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


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