Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dose response effect of a new adenosine analogue, GR79236 (N-[1S trans-2-hydroxycyclopentyl] adenosine) upon insulin sensitivity was examined in human adipocytes. The influence of adenosine upon insulin sensitivity for suppression of lipolysis and stimulation of glucose transport was examined. Removal of adenosine by use of adenosine deaminase stimulated lipolysis to the same extent as did 10(-9) M noradrenaline. GR79236 brought about dose dependent inhibition of lipolysis with half-maximal effect at 11.3 +/- 7.8 x 10(-9) M. When lipolysis was stimulated by noradrenaline alone the subsequent inhibition of lipolysis brought about by GR79236 was significantly greater than that of insulin. To examine adenosine effects on the insulin signalling pathway separately from those on lipolysis, the insulin sensitivity of glucose transport was examined. Removal of adenosine brought about a small but significant increase in the concentration of insulin required for half-maximal stimulation of glucose transport. Adenosine agonists offer promise as new agents for the modulation of metabolism in diabetes and other states of insulin resistance.
Mol Cell Biochem 1995 Mar 23
PMID:Adenosine effects upon insulin action on lipolysis and glucose transport in human adipocytes. 762 86

Nucleoside transport may play a critical role in successful intracellular parasitism by Toxoplasma gondii. This protozoan is incapable of de novo purine synthesis, and must salvage purines from the host cell. We characterized purine transport by extracellular T. gondii tachyzoites, focusing on adenosine, the preferred salvage substrate. Although wild-type RH tachyzoites concentrated [3H]adenosine 1.8-fold within 30 s, approx. half of the [3H]adenosine was converted to nucleotide, consistent with the known high parasite adenosine kinase activity. Studies using an adenosine kinase deficient mutant confirmed that adenosine transport was non-concentrative. [14C]Inosine, [14C]hypoxanthine and [3H]adenine transport was also rapid and non-concentrative. Adenosine transport was inhibited by dipyridamole (IC50 approx. 0.7 microM), but not nitrobenzylthioinosine (15 microM). Transport of inosine, hypoxanthine and adenine was minimally inhibited by 10 microM dipyridamole, however. Competition experiments using unlabeled nucleosides and bases demonstrated distinct inhibitor profiles for [3H]adenosine and [14C]inosine transport. These results are most consistent with a single, dipyridamole-sensitive, adenosine transporter located in the T. gondii plasma membrane. Additional permeation pathways for inosine, hypoxanthine, adenine and other purines may also be present.
Mol Biochem Parasitol 1995 Mar
PMID:Toxoplasma gondii tachyzoites possess an unusual plasma membrane adenosine transporter. 763 15

Porcine brain-derived microvascular endothelial cells (BMEC) express the mRNA of the polypeptide mitogen vascular permeability factor/vascular endothelial growth factor (VPF/VEGF). The VEGF mRNA expression in BMEC could be upregulated 2.5 fold after 6 h of treatment with 5 microM adenosine and adenosine agonists. Adenosine A1 and A2 receptor antagonists completely abolished the upregulation of the VEGF mRNA caused by adenosine. Agents like forskolin and cAMP phosphodiesterase inhibitors which are known to increase the cAMP level decreased the VEGF mRNA expression slightly whereas agents like phorbolester which activate the proteinkinase C (PKC) pathway enhanced the VEGF mRNA expression 3.2 fold. The specific inhibitor of the PKC bisindolymaleimide (BIM) abolished the upregulation of the VEGF mRNA by adenosine completely. The BMEC conditioned medium stimulated the proliferation of BMEC itself and Western blot analysis of the BMEC conditioned medium using a polyclonal antibody to human VEGF showed one band at 18 kDa which was slightly upregulated after treatment with adenosine. Results suggest that the effect of adenosine on the VEGF mRNA expression is mediated via the A1 receptor and that an activation of the PKC may be involved in the observed effects of adenosine on the VEGF mRNA expression. VEGF produced by BMEC and which is inducible by adenosine may function via the autocrine pathway and may be involved in repair reactions of brain blood vessels and/or the maintenance of these cells.
Brain Res Mol Brain Res 1995 Jan
PMID:Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. 770 68

To determine whether dilation of large coronary arteries normalizes shear during increased flow following brief occlusion, six dogs were instrumented to measure aortic and left ventricular pressures, left circumflex coronary artery external diameter, and coronary blood flow. The coronary artery was occluded for 15 or 30 s. Data were obtained before and after blockade of EDRF synthesis with nitro-L-arginine. Internal coronary artery diameter and wall shear were calculated on a moment-to-moment basis and the area under the flow curve was measured. Peak flow and shear rate were unaffected by NLA or by the occlusion duration. Flow curve area increased with the duration of occlusion. Internal and external diameters increased significantly for 15 s occlusions before NLA (by 4 +/- 1% in external diameter and by 11 +/- 4% in internal diameter) and for 30 s occlusions before NLA (by 5 +/- 1% in external diameter and by 14 +/- 5% in internal diameter) but not after NLA. Adenosine infusions of 0.05, 0.10, 0.50, and 1.0 mumol/kg/min were also used to dilate the coronary arteries. With each infusion, flow, shear and diameter were allowed to reach steady state. Steady state shear was reduced only slightly and did not approach the baseline state. We conclude that increased shear rate causes an increase in coronary artery diameter which is EDRF dependent. Increased coronary artery diameter during reactive hyperemia and adenosine infusions did not normalize wall shear.
J Mol Cell Cardiol 1994 Dec
PMID:Role of EDRF in the regulation of shear rate in large coronary arteries in conscious dogs. 773 Oct 57

The involvement of guanine nucleotide-binding regulatory proteins (G-proteins) and adenylyl cyclase in the gonadotropin stimulation of cAMP was investigated using crude membrane fractions from granulosa cells of amago salmon (Oncorhynchus rhodurus) postvitellogenic ovarian follicles. Although cholera toxin-catalyzed ADP ribosylation occurred in 45- and 50-kDa proteins, only the former was recognized by an antibody against the alpha-subunit of Gs. With pertussis toxin, only the 41-kDa protein was ADP-ribosylated. This 41-kDa protein was recognized by an antibody against the alpha-subunit of Gi. Partially purified chum salmon gonadotropin (SGA) stimulated adenylyl cyclase activity in crude membrane preparations of granulosa cells only in the presence of pertussis toxin in the incubation medium. Adenosine inhibited adenylyl cyclase in the presence of GTP and pertussis toxin reversed it. Unlike SGA, forskolin, which acts upon adenylyl cyclase without G-protein interaction, markedly stimulated adenylyl cyclase activity in the absence of pertussis toxin. These results provide evidence that both stimulatory (Gs) and inhibitory (Gi) regulation by adenylyl cyclase operates in the granulosa cells of amago salmon postvitellogenic ovarian follicles. It is possible that, although a stimulatory receptor interacts with Gs, its activity is influenced by the functional state of Gi.
Mol Cell Endocrinol 1994 Oct
PMID:G-proteins and adenylyl cyclase in ovarian granulosa cells of amago salmon (Oncorhynchus rhodurus). 782 21

The effects of preconditioning, adenosine and dipyridamole in protecting the systolic and diastolic alterations of myocardial stunning in rabbit hearts were studied. Isovolumic left ventricular developed pressure (LVDP), and end diastolic pressure (LVEDP) were measured. The time constant of relaxation (T) was calculated. Isolated rabbit hearts were subject to 15 min of global ischemia (37 degrees C) followed by 30 min of reperfusion. LVDP and LVEDP stabilized to 55 +/- 5% and 320 +/- 28% of control values respectively (stunned group) T increased early in reperfusion (from 48.2 +/- 3.9 to 97.2 +/- 10 ms P < 0.05) but returned to control value late in reperfusion. When hearts were preconditioned by a single cycle of 5 min of ischemia LVDP and LVEDP stabilized at 89 +/- 3% and 162 +/- 34% of preischemic values respectively (P < 0.05 with respect to stunned group). The change in T was attenuated (62 +/- 6 ms at 5 min of reperfusion, P < 0.05 with respect to stunned group). Hearts treated either with adenosine (800 micrograms/min) or the nucleoside transport blocker dipyridamole (4 micrograms/min) previously to the ischemia, recovered their LVDP to 86 +/- 1% and 82 +/- 3% of preischemic values, respectively (P < 0.05 with respect to stunned group). Adenosine and dipyridamole also attenuated the increase in LVEDP (195 +/- 12% and 197 +/- 10% respectively, P < 0.05 with respect to stunned group).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1994 Oct
PMID:Adenosine and dipyridamole mimic the effects of ischemic preconditioning. 786

Adenosine analogs substituted in the 2-position with arylamino groups have been found to have high affinity and selectivity for A2a adenosine receptors. Two such compounds, 2-[2-(4-aminophenyl)ethylamino]adenosine and 2-[2-4-amino-3-iodophenyl)ethylamino]adenosine (I-APE), were synthesized and found to be potent coronary vasodilators (ED50 < 3 nm). These compounds bind weakly to A1 adenosine receptors of rat cortex (Ki > 150 nM). 125I-APE was synthesized and the new radioligand was found to bind to two affinity states of rat striatal A2a adenosine receptors (Kd = 1.3 +/- 0.1 nM and 19 +/- 4.5 nM). The high affinity site represents a previously unrecognized small (15-20%) fraction of A2a adenosine receptors coupled to G proteins. Guanosine 5'-O-(3-thio)triphosphate (GTP gamma S) reduces specific binding of 125I-APE half-maximally at a concentration of 45 +/- 2 nM. [3H]CGS21680 also binds to two affinity states of A2a receptors on striatal membranes (Kd = 3.9 +/- 0.9 and 51 +/- 5.5 nM), although in previous studies single Kd values ranging from 5 to 15 nM have been reported. This high affinity site is substantiated by the finding that the IC50 of CGS21680 in competition with 125I-APE binding to striatal membranes is shifted leftward in membranes diluted for 4 min before filtration, to selectively dissociate radioligand from low affinity receptors. Assuming that agonist radioligands bind to both coupled and uncoupled forms of striatal A2a adenosine receptors, we could simulate with the computer the finding that the decrease in specific binding induced by GTP gamma S (100 microM) is variable and depends on radioligand concentration, ranging from 20 to 90%. Unlike 125I-APE, [3H]CGS21680 is charged at physiological pH, and treatment of membranes with the pore-forming antibiotic alamethicin uncovers cryptic [3H]CGS21680 but not 125I-APE binding sites. We conclude that the GTP gamma S-sensitive high affinity form of the A2a adenosine receptor can be preferentially labeled by 125I-APE, due to both its high specific activity and its physicochemical properties. Possible functional manifestations of poor coupling of A2a adenosine receptors to G proteins are discussed.
Mol Pharmacol 1995 Feb
PMID:Characterization of two affinity states of adenosine A2a receptors with a new radioligand, 2-[2-(4-amino-3-[125I]iodophenyl)ethylamino]adenosine. 787 39

Adenosine uptake via nucleoside transporters is inhibited when S49 and NG108-15 cell lines cells are exposed to ethanol. This inhibition leads to an accumulation of extracellular adenosine that binds to adenosine A2 receptors and increases cAMP production. Subsequently, there is a heterologous desensitization of receptors coupled to adenylyl cyclase for which adenosine also is required. There are multiple classes of facilitative and concentrative nucleoside transporters that could be inhibited by ethanol to initiate this cascade of events. In this paper, we establish that adenosine uptake by only one type of nucleoside transporter, an NBMPR-sensitive facilitative transporter, is inhibited by ethanol. There is no effect on other classes of nucleoside transporters even when present in the same cell. Thus, ethanol-induced extracellular accumulation of adenosine results specifically from inhibition of NBMPR-sensitive facilitative nucleoside transporters. We also find that human lymphocytes express only facilitative nucleoside transporters and that the NBMPR-sensitive type is predominant. Thus, inhibition of this type of transporter by ethanol may be related to the desensitization of cAMP signal transduction that we have reported in lymphocytes from alcoholics.
Mol Pharmacol 1993 Nov
PMID:Inhibition of adenosine uptake by ethanol is specific for one class of nucleoside transporters. 790 30

Left atria were isolated from rats made hypothyroid by adding propylthiouracil to their drinking water, such rats after saturating doses of thyroid hormones, and from control rats. Isoproterenol (ISO; 1 microM) increased the values of developed tension (DT), maximal rate of tension development (+dt/dt) and tension fall (-dT/dt). The effect was largest in hypothyroid and lowest in hyperthyroid atria. The adenosine A1-receptor agonist N6-(phenylisopropyl)-adenosine (PIA) had a powerful negative inotropic effect in ISO-stimulated atria. The effects of PIA on +dT/dt, -dT/dt and DT were enhanced in hypothyroidism. Adenosine receptor number was not decreased. The amount of total Gi-like proteins was estimated by pertussis toxin labeling. The amounts of Gi2 and Gi3 were estimated in Western blots using such antisera raised in rabbits against peptides corresponding to parts of their sequences, using purified recombinant alpha subunits as standards. The amounts of low and high molecular weight forms of Gs were estimated by cholera toxin labeling Gi2, Gi3 and pertussis toxin substrate concentrations were slightly lower in the hypothyroid animals, while the amounts of both forms of Gs per mg of protein were only half of those in euthyroid rat atria. The levels of Gi2 and Gi3 were greatly elevated as compared to Gs as membrane marker. These changes were reversed by treatment of the hypothyroid rats with thyroid hormones. In conclusion, the present results show an enhanced negative inotropic effect of an adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1994 Apr
PMID:Enhanced negative inotropic effect of an adenosine A1-receptor agonist in rat left atria in hypothyroidism. 791 34

The potential of 8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-[3H] methylxanthine ([3H]Kf17837S) as a highly selective antagonist radioligand for the adenosine A2A receptor was examined and compared with the properties of the adenosine A2A receptor agonist radioligand 2-[p-(2-[3H]carboxyethyl)phenethylamino]-5'-N-ethyl- carboxamidoadenosine ([3H]CGS21680). [3H]KF17837S specific binding to rat striatal membranes was saturable and reversible. Saturation studies showed that the binding of [3H]KF17837S occurred at a single site, with high affinity (Kd, 7.1 +/- 0.91 nM) and limited capacity (Bmax, 1.3 +/- 0.23 pmol/mg of protein). Adenosine receptor antagonist ligands competed with the binding of 1 nM [3H]KF17837S with the following order of activity: CGS15943 > KF17837S > N-[2-(dimethylamino)ethyl]-N-methyl- 4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesul fonamide > or = xanthine amine congener > 8-cyclopentyl-1,3-dipropylxanthine > 8-(noradamantan-3-yl)-1,3-dipropylxanthine > caffeine. Adenosine receptor agonists inhibited [3H] KF17837S binding in the following order: 5'-N-ethylcarboxamidoadenosine > or = CGS21680 > 2-phenylaminoadenosine > or = (R)- N6-phenylisopropyladenosine > N6-cyclopentyladenosine > (S)- N6-phenylisopropyladenosine. The Ki values of the antagonists for [3H]KF17837S binding and the rank order of potency were similar to those for [3H]CGS21680 binding. The affinities of the agonists were lower with [3H]KF17837S binding than with [3H] CGS21680 binding. However, a strong positive correlation (r = 0.98) was observed between the pharmacological profiles for these two radioligand assays. The inhibition curve for CGS21680 was best fitted to a two-component binding model and addition of GTP shifted the inhibition curve to the right, suggesting that [3H]KF17837S labeled two agonist coupling states. Other pharmacological agents had negligible affinities for the [3H]KF17837S binding site. Autoradiographic study of [3H]KF17837S binding using rat brain sections revealed that the binding site was highly enriched in the striatal region. These data indicate that [3H] KF17837S labels the adenosine A2A receptor in rat brain.
Mol Pharmacol 1994 Nov
PMID:Binding of [3H]KF17837S, a selective adenosine A2 receptor antagonist, to rat brain membranes. 796 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>