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)

Adenosine has been implicated in various aspects of pituitary function but little is known of its role in the regulation of thyrotrophin (TSH) release. This study examined the effects of adenosine deaminase (ADA, which provokes adenosine breakdown) and selective adenosine-receptor ligands on the secretion of immunoreactive (ir-) TSH and prolactin (PRL) by rat anterior pituitary segments in vitro. ADA (5 U/ml) stimulated the release of both hormones (P<0.01) as also did the selective adenosine A1-receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 & 1 nM, P<0.01); the responses to ADA were inhibited by an A1-receptor agonist, N6-cyclohexyladenosine (0.1-10 nM, P<0.01). A non-selective A1/A2-receptor agonist, N-cyclopropylcarboxamidoadenosine (1-100 nM) had mixed effects on ir-TSH release. However, the A2A-receptor selective agonist, CGS 21680 (1-100 nM) increased ir-TSH (P<0.05) and ir-PRL release (P<0.01); its effects on ir-TSH were blocked by concentrations of DPCPX (100 nM, P<0.01) sufficient to antagonize A2-receptors. These data suggest that adenosine acts via A1-receptors to tonically suppress ir-PRL and ir-TSH release but that A2A-receptor activation enhances the release of both hormones.
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PMID:Roles for adenosine A1- and A2-receptors in the control of thyrotrophin and prolactin release from the anterior pituitary gland. 993 May 81

[35S]Guanosine 5'-(gamma-thio)triphosphate autoradiography is a novel technique to detect receptor-dependent activation of G-proteins in brain tissue sections. While an increasing number of reports using this approach are beginning to appear, little effort has been directed to the identification of factors responsible for the heterogeneously distributed [35S]guanosine 5'-(gamma-thio)triphosphate signal in basal conditions. The present study demonstrates that endogenously formed adenosine generates a widespread and prominent adenosine A1 receptor-dependent signal in basal conditions using this technique. Treatment of rat brain tissue sections with the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine dose-dependently (EC50 < 10 nM) suppressed basal [35S]guanosine 5'-(gamma-thio)triphosphate binding in a region-specific manner, an effect fully mimicked by the adenosine-depleting enzyme adenosine deaminase, and less so by the A1 antagonist cirsimarin and by caffeine. That adenosine was continuously formed during the incubation is supported by the constant requirements of adenosine deaminase in order to suppress basal radioligand binding and further by the fact that low micromolar concentrations of adenine nucleotides evoked only adenosine-mimicking and fully 8-cyclopentyl-1,3-dipropylxanthine-sensitive binding responses. In the presence of adenosine deaminase, all responses to adenine nucleotides were abolished, indicating that prior conversion to adenosine was required. Upon stimulation, this technique selectively detected A1 receptor-activated G-proteins, as the non-selective agonists adenosine and 2-chloroadenosine and the A1-selective agonist N6-p-sulfophenyladenosine all evoked only 8-cyclopentyl-1,3-dipropylxanthine-sensitive responses in identical gray matter areas, and also in several white matter areas such as the corpus callosum, anterior commissure, optic tract and cerebellar white matter. Dose-response studies revealed region-specific differences in the magnitude of A1 receptor-stimulated G-protein activation, with the highest response (nine-fold over basal) detectable in the hippocampus. No response to the A2A-selective agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5'-N-et hylcarboxamidoadenosine or the A3-selective agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide was detected in any region. These data reveal that a significant amount of noise inherent to [35S]guanosine 5'-(gamma-thio)triphosphate autoradiography can be eliminated by removal of the adenosine signal, a step likely facilitating detection of responses to other receptors. Furthermore, the data establish [35S]guanosine 5-(gamma-thio)triphosphate autoradiography as a novel and selective approach to directly assess A1 receptor-G-protein coupling in anatomically defined regions of the central nervous system.
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PMID:Selective detection of adenosine A1 receptor-dependent G-protein activity in basal and stimulated conditions of rat brain [35S]guanosine 5'-(gamma-thio)triphosphate autoradiography. 1033 96

The role of adenosine receptor in regulation of insulin-induced activation of phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B was studied in isolated rat adipocytes. Rat adipocytes are known to spontaneously release adenosine, which in turn binds and stimulates the adenosine A1 receptors on the cells. In the present study, we observed that degradation of this adenosine by adenosine deaminase attenuated markedly the insulin-induced accumulation of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), a product of PI 3-kinase. p-Aminophenylacetyl xanthine amine congener (PAPA-XAC), an inhibitor of the adenosine A1 receptor, also inhibited the insulin-induced PtdIns(3,4,5)P3 accumulation. When extracellular adenosine was inactivated by adenosine deaminase, phenylisopropyladenosine, an adenosine A1 receptor agonist, potentiated the insulin-induced accumulation of PtdIns(3,4,5)P3. Insulin-induced activation of protein kinase B, the activity of which is controlled by the lipid products of PI 3-kinase, was also potentiated by adenosine. Prostaglandin E2, another activator of a pertussis toxin-sensitive GTP-binding protein in these cells, potentiated the insulin actions. Thus, the receptors coupling to the GTP-binding protein were found to positively regulate the production of PtdIns(3,4,5)P3, a putative second messenger for insulin actions, in physiological target cells of insulin.
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PMID:Enhancement by adenosine of insulin-induced activation of phosphoinositide 3-kinase and protein kinase B in rat adipocytes. 1039 87

We studied 273 subjects with non-insulin-dependent diabetes mellitus (NIDDM) from the population of Penne, Italy. A low proportion of the adenosine deaminase (ADA)*2 allele is observed in NIDDM subjects with a body mass index (BMI) of 25 kg/m2 or less. On the contrary, a high proportion of this allele is observed in NIDDM patients with a BMI higher than 34 kg/m2. In the intermediate BMI class, the proportion of ADA*2 alleles does not differ significantly from that of normal subjects from the same population. No significant effect on the relation between ADA and BMI has been observed for the following variables: sex, age at the time of study, age at onset, therapy with insulin, and dyslipidemia. A borderline effect has been observed for the duration of disease. Several lines of experimental evidence suggest that an excess of adenosine A1 receptor activity may contribute to adiposity in NIDDM. ADA is a polymorphic enzyme that irreversibly deaminates adenosine to inosine, contributing to the regulation of intracellular and extracellular concentrations of adenosine. Since the activity of genotypes carrying the ADA*2 allele is lower than that of the more common genotype ADA*1/*1, genetic variability of the enzyme could contribute to degree of obesity in NIDDM. Our data also support attempts to ameliorate the metabolic control of diabetes through pharmacological modulation of adenosine receptors.
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PMID:Adenosine deaminase and body mass index in non-insulin-dependent diabetes mellitus. 1045 55

We investigated the effect of adenosine A1 receptors on the release of acetylcholine (ACh) and GABA, and on the intracellular calcium concentration ([Ca2+]i) response in cultured chick amacrine-like neurons, stimulated by KCl depolarization. The KCl-induced release of [3H]ACh, but not the release of [14C]GABA, was potentiated when adenosine A1 receptor activation was prevented by perfusing the cells with adenosine deaminase (ADA) or with 1,3-dipropyl-8-cycloentylxanthine (DPCPX). The changes in the [Ca2+]i induced by KCl depolarization, measured in neurite segments of single cultured cells, were also modulated by endogenous adenosine, acting on adenosine A1 receptors. Our results show that adenosine A1 receptors inhibit Ca2+ entry coupled to ACh release, but not to the release of GABA, suggesting that the synaptic vesicles containing each neurotransmitter are located in different zones of the neurites, containing different VSCC and/or different densities of adenosine A1 receptors.
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PMID:Adenosine A1 receptors inhibit Ca2+ channels coupled to the release of ACh, but not of GABA, in cultured retina cells. 1066 90

1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and beta-adrenoceptor activation with isoproterenol were studied in wild-type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC50 6.4+/-0.2) and vasodilatation (pEC50 7.9+/-0.1; minimal resistance 2.2+/-0.2 mmHg/mL per min per g). The A1 receptor-mediated bradycardia was 20-fold more sensitive in transgenic hearts (pEC50 7.7+/-0.2), whereas coronary vasoactivity of 2-ClAdo was unaltered (pEC50 7.6+/-0.1). 3. beta-Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5+/-0.2; maximal rate 594+/-23 b.p.m.) and produced vasodilation (pEC50 8.7+/-0.1; minimal resistance 1.7 +/-0.2 mmHg/ml, per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653+/-27 b.p.m.) without altering potency (pEC50 8.5+/-0.1). Antagonism of A1 receptors with 10nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695+/-26b.p.m.) without altering potency (pEC50 8.3+/-0.1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during beta-adrenoceptor stimulation by 35% (to 381 +/-28 b.p.m.) without altering potency (pEC50 8.4+/-0.2). At 10nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484+/-36 b.p.m.) without altering potency (pECs50 8.3+/-0.2). 5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the beta-adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of beta-adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non-competitively inhibits effector mechanisms activated by beta-adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
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PMID:Chronotropic and vasodilatory responses to adenosine and isoproterenol in mouse heart: effects of adenosine A1 receptor overexpression. 1074 45

Superfusion of rat hippocampal slices with ATP induces a form of facilitation that has been poorly characterised. The present study has confirmed that at low concentrations of ATP (10 microM or less), an initial depression of evoked potential size is followed by a rebound facilitation which is not reproduced by alphabeta-methyleneATP, betagamma-methyleneATP, or the dinucleotide P1,P6-diadenosine hexaphosphate. The post-ATP facilitation could be prevented by the adenosine A1 receptor antagonists 8-phenyltheophylline or 1,3-dipropyl-8-cyclopentyltheophylline (50 nM), or superfusion of adenosine deaminase. The adenosine A2A receptor antagonist 8-(chlorostyryl)-caffeine did not affect the inhibition but prevented the post-ATP facilitation. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid prevented the establishment of post-ATP facilitation. The post-ATP facilitation was also blocked by suramin at a concentration (50 microM) that does not block glutamate receptors. Suramin prevented the induction but not the maintenance phase of the post-ATP facilitation. The repeated induction of post-ATP facilitation by bursts of electrical stimulation designed to saturate the normal mechanisms of long-term potentiation prevented the induction of post-ATP facilitation. However, repeated applications of ATP to achieve saturation of its receptor did not prevent the subsequent induction of electrically evoked long-term potentiation. It is concluded that ATP can induce a form of synaptic facilitation which resembles only partially that induced by electrical stimulation and which may require the simultaneous activation of P1 and P2 receptors.
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PMID:Characterisation of ATP-induced facilitation of transmission in rat hippocampus. 1110 29

The aim of the present study was to gain insight into the signaling pathway used by leptin to stimulate lipolysis. The lipolytic rate of white adipocytes from sex- and age-matched lean (+/+) and fa/fa rats was determined in the absence or presence of leptin together with a number of agents acting at different levels of the signaling cascade. Leptin did not modify FSK-, dbcAMP-, and IBMX-stimulated lipolysis. Lipolysis can also be maximally stimulated by lowering media adenosine levels with adenosine deaminase (ADA), i.e., in the ligand-free state. Although ADA produced near maximal lipolysis in adipocytes of lean animals, only half of the maximal lipolytic rate (50.9+/-3.2%) was achieved in fat cells from fa/fa rats (P=0.0034). In adipocytes from lean animals preincubated with ADA, leptin caused a concentration-related stimulation of lipolysis (P=0.0001). However, leptin had no effect on the lipolytic activity of adipocytes in the ligand-free state from fa/fa rats. The adenosine A1 receptor agonist CPA effectively inhibited basal lipolysis in both lean and obese adipocytes (P=0.0001 and P=0.0090, respectively). Leptin had no effect on the lipolytic rate of adipocytes isolated from fa/fa rats and preincubated with CPA. When adipocytes were incubated with the A1 receptor antagonist DPCPX, a significant increase in glycerol release was observed in fa/fa fat cells (P=0.009), whereas cells isolated from lean rats showed no differences to ADA-stimulated lipolysis. After pretreatment with PTX, which inactivates receptor-mediated Gi function, adipocytes of obese rats became as responsive to the stimulatory actions of ISO as cells from lean rats (P=0.0090 vs. ISO in fa/fa rats; P=0.2416 vs. lean rats, respectively). PTX treatment of lean cells, however, did not alter their response to this lipolytic agent. It can be concluded that the lipolytic effect of leptin is located at the adenylate cyclase/Gi proteins level and that leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes.
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PMID:Leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes. 1115 49

1. It is well established that presynaptic adenosine A1-receptor activation inhibits acetylcholine (ACh) release in the guinea-pig ileum. The present study extends this observation and examines a possible role for endogenous adenosine in modulating cholinergic nerve function. 2. The actions of the adenosine uptake blocker, dipyridamole, the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (EHNA) and the A1-receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were examined on electrically evoked neurogenic, cholinergic twitch contractions of the guinea-pig ileum. Some additional studies measuring [3H]-ACh release were also performed. 3. Adenosine and the selective A1-receptor agonist, 2-chloroadenosine (2-CA), inhibited electrically evoked contractions and, in the case of 2-CA, [3H]-ACh release. The actions were antagonized by DPCPX. At low concentrations, dipyridamole and EHNA enhanced the effect of adenosine causing a leftward shift of the concentration-response curve. In contrast, inhibition induced by 2-CA was unaffected by either dipyridamole or EHNA. 4. When applied alone at higher concentrations, EHNA and dipyridamole produced a concentration-dependent suppression of cholinergic neurotransmission. In both cases, the effect could be reversed by DPCPX. At the same concentration, DPCPX alone produced a small but consistent increase in twitch height and [3H]-ACh release. 5. The data confirm the existence of inhibitory presynaptic adenosine A1-receptors modulating cholinergic nerve function in the guinea-pig ileum and suggests that these receptors can be activated by endogenous adenosine released either as adenosine itself or as an ATP metabolite.
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PMID:Activation of presynaptic A1-receptors by endogenous adenosine inhibits acetylcholine release in the guinea-pig ileum. 1142 76

The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure during endotoxemia. CGS 21680 completely inhibited endotoxin-induced release of TNFalpha, augmented sympathetic activity and PRA, and increased +dP/dtmax and +dP/dtmax/VPSP in the absence and presence of endotoxin. The present study provides strong evidence that inhibition of adenosine deaminase reduces cytokine release in vivo without producing significant hemodynamic and cardiac effects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cytokine release induced by endotoxin. Further studies are warranted to determine the impact of these effects on cardiac function and hemodynamics in the late phase of endotoxemia.
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PMID:Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats. 1153 Oct 21


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