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Adenosine Receptors (adenosine + receptor)
Terms modified by Adenosine Receptors Selected AbstractsThe Discovery and Synthesis of Novel Adenosine Receptor (A2A) Antagonists.CHEMINFORM, Issue 28 2005Julius J. Matasi Abstract For Abstract see ChemInform Abstract in Full Text. [source] 4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a New Potential Fluorescent Probe for Studying A1 -Adenosine Receptor.CHEMINFORM, Issue 7 2003Marco Macchia Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Synthesis and Biological Data of 4-Amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo [3,4-b]pyridine-5-carboxylic Acid Ethyl Esters, a New Series of A1 -Adenosine Receptor (A1AR) Ligands.CHEMINFORM, Issue 5 2002Silvia Schenone Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Agonist-Induced Internalization and Recycling of the Human A3 Adenosine ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 4 2000Resensitization, Role in Receptor Desensitization Abstract: A3 adenosine receptors have been proposed to play an important role in the pathophysiology of cerebral ischemia with a regimen-dependent nature of the therapeutic effects probably related to receptor desensitization and down-regulation. Here we studied the agonist-induced internalization of human A3 adenosine receptors in transfected Chinese hamster ovary cells, and then we evaluated the relationship between internalization and signal desensitization and resensitization. Binding of N6 -(4-amino-3-[125I]iodobenzyl)adenosine-5,- N -methyluronamide to membranes from Chinese hamster ovary cells stably transfected with the human A3 adenosine receptor showed a profile typical of these receptors in other cell lines (KD = 1.3 ± 0.08 nM; Bmax = 400 ± 28 fmol/mg of proteins). The iodinated agonist, bound at 4°C to whole transfected cells, was internalized by increasing the temperature to 37°C with a rate constant of 0.04 ± 0.034 min -1. Agonist-induced internalization of A3 adenosine receptors was directly demonstrated by immunogold electron microscopy, which revealed the localization of these receptors in plasma membranes and intracellular vesicles. Moreover, short-term exposure of these cells to the agonist caused rapid desensitization as tested in adenylyl cyclase assays. Subsequent removal of the agonist led to restoration of the receptor function and recycling of the receptors to the cell surface. The rate constant of receptor recycling was 0.02 ± 0.0017 min -1. Blockade of internalization and recycling demonstrated that internalization did not affect signal desensitization, whereas recycling of internalized receptors was implicated in the signal resensitization. [source] A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and TranslocationBRAIN PATHOLOGY, Issue 4 2003Ester Angulo Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD. [source] Adenosine receptors: promising targets for the development of novel therapeutics and diagnostics for asthmaFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2006Cristina Russo Abstract Interest in the role of adenosine in asthma has escalated considerably since the early observation of its powerful bronchoconstrictor effects in asthmatic but not normal airways. A growing body of evidence has emerged in support of a proinflammatory and immunomodulatory role for the purine nucleoside adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma. The fact that adenosine enhances mast cell allergen-dependent activation, that elevated levels of adenosine are present in chronically inflamed airways, and that adenosine given by inhalation cause dose-dependent bronchoconstriction in subjects with asthma emphasizes the importance of adenosine in the initiation, persistence and progression of these common inflammatory disorders of the airways. These distinctive features of adenosine have been recently exploited in the clinical and research setting to identify innovative diagnostic applications for asthma. In addition, because adenosine exerts its multiple biological activities by interacting with four adenosine receptor subtypes, selective activation or blockade of these receptors may lead to the development of novel therapies for asthma. [source] G protein-independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cellsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2007Toshihide Tabata Adenosine receptors (ARs) are G protein-coupled receptors (GPCRs) mediating the neuromodulatory actions of adenosine that influence emotional, cognitive, motor, and other functions in the central nervous system (CNS). Previous studies show complex formation between ARs and metabotropic glutamate receptors (mGluRs) in heterologous systems and close colocalization of ARs and mGluRs in several central neurons. Here we explored the possibility of intimate functional interplay between Gi/o protein-coupled A1 -subtype AR (A1R) and type-1 mGluR (mGluR1) naturally occurring in cerebellar Purkinje cells. Using a perforated-patch voltage-clamp technique, we found that both synthetic and endogenous agonists for A1R induced continuous depression of a mGluR1-coupled inward current. A1R agonists also depressed mGluR1-coupled intracellular Ca2+ mobilization monitored by fluorometry. A1R indeed mediated this depression because genetic depletion of A1R abolished it. Surprisingly, A1R agonist-induced depression persisted after blockade of Gi/o protein. The depression appeared to involve neither the cAMP-protein kinase A cascade downstream of the alpha subunits of Gi/o and Gs proteins, nor cytoplasmic Ca2+ that is suggested to be regulated by the beta-gamma subunit complex of Gi/o protein. Moreover, A1R did not appear to affect Gq protein which mediates the mGluR1-coupled responses. These findings suggest that A1R modulates mGluR1 signalling without the aid of the major G proteins. In this respect, the A1R-mediated depression of mGluR1 signalling shown here is clearly distinguished from the A1R-mediated neuronal responses described so far. These findings demonstrate a novel neuromodulatory action of adenosine in central neurons. [source] Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti,tumor necrosis factor , but not methotrexateARTHRITIS & RHEUMATISM, Issue 10 2009Katia Varani Objective To investigate A1, A2A, A2B, and A3 adenosine receptors in lymphocytes and neutrophils from patients with early rheumatoid arthritis (ERA) as well as from RA patients treated with methotrexate (MTX) or anti,tumor necrosis factor , (anti-TNF,), as compared with those in age-matched healthy controls, and to examine correlations between the status and functionality of adenosine receptors and TNF, release and NF-,B activation. Methods Adenosine receptors were analyzed by saturation binding assays and Western blot analyses. We investigated the potency of typical A2A and A3 agonists in the production of cAMP in control subjects, ERA patients, and RA patients treated with MTX or anti-TNF,. In a separate cohort of RA patients, TNF, release and NF-,B activation were evaluated in plasma and nuclear extracts, respectively. Results In ERA patients, we found a high density and altered functionality of A2A and A3 receptors. The binding and functional parameters of A2A and A3 receptors normalized after anti-TNF,, but not MTX, treatment. TNF, release was increased in ERA patients and in MTX-treated RA patients, whereas in anti-TNF,,treated RA patients, release was comparable to that in the controls. NF-,B activation was elevated in ERA patients and in MTX-treated RA patients. Anti-TNF, treatment mediated decreased levels of NF-,B activation. Conclusion A2A and A3 receptor up-regulation in ERA patients and in MTX-treated RA patients was associated with high levels of TNF, and NF-,B activation. Treatment with anti-TNF, normalized A2A and A3 receptor expression and functionality. This new evidence of A2A and A3 receptor involvement opens the possibility of exploiting their potential role in human diseases characterized by a marked inflammatory component. [source] Adenosine modulates cell growth in baby hamster kidney (BHK) cellsBIOFACTORS, Issue 4 2000Rashmi A. Mittal Abstract Adenosine is known to modulate cell growth in a variety of mammalian cells either via the activation of receptors or through metabolism. We investigated the effect of adenosine on Baby Hamster Kidney (BHK) cell growth and attempted to determine its mechanism of modulation. In wild-type BHK cells, adenosine evoked a biphasic response in which a low concentration of adenosine (1± 150;5 ,M) produced an inhibition of colony formation but at higher concentrations (up to 50 ,M) this inhibition was progressively reversed. However, no biphasic response was observed in an ± 147;adenosine kinase± 148; deficient BHK mutant, ± 147;5a± 148;, which suggests that adenosine kinase plays an important role in the modulation of growth response to adenosine. Adenosine receptors did not appear to have a role in regulating cell growth of BHK cells. Specific A1 and A2 receptor antagonists were unable to reverse the effect of adenosine on cell growth. Even though a specific A3 adenosine receptor antagonist MRS-1220 partly reversed the inhibition in colony formation at 1 ,M adenosine, it also affected the transport of adenosine. Thus adenosine transport and metabolism appears to play the major role in this modulation of cell growth as 5,-amino-5,-deoxyadenosine, an adenosine kinase inhibitor, reversed the inhibition of cell growth observed at 1 ,M adenosine. These results, taken together, would suggest that adenosine modulates cell growth in BHK mainly through its transport and metabolism to adenine nucleotides. [source] Adenosine receptors: novel targets for drug development in allergic rhinitisCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2007M. G. Matera First page of article [source] Induction of apoptosis by A3 adenosine receptor agonist N6 -(3-iodobenzyl)-adenosine-5,- N -methylcarboxamide in human leukaemia cells: a possible involvement of intracellular mechanismACTA PHYSIOLOGICA, Issue 2 2010P. Mlejnek Abstract Aim:, The sensitivity of cancer cells which exhibit multi-drug resistance phenotype to A3 adenosine receptor (A3AR) agonist N6 -(3-iodobenzyl)-adenosine-5,- N -methylcarboxamide (IB-MECA) was studied. Methods:, To establish direct relationship between P-glycoprotein (P-gp, ABCB1 and MDR1) expression and IB-MECA induced cell death, a straightforward method for precise estimation of intracellular level of this A3AR agonist was developed. Results:, We subjected three human leukaemia cell lines HL-60, K562 and K562/HHT to treatment with micromolar concentrations of IB-MECA. Although all cell lines used expressed A3AR, there was a large difference in their sensitivity to IB-MECA. While HL-60 and K562 cells were almost equally sensitive, the K562/HHT cells, which exhibit a multi-drug resistance phenotype because of overexpression of P-gp, were significantly more resistant. We found that the intracellular level of IB-MECA in K562/HHT cells was approx. 10 times lower than those in HL-60 or K562 cells. Inhibitors of P-gp, including cyclosporine A (CsA) and verapamil (Vpa), increased the intracellular level of IB-MECA and reversed the resistance of K562/HHT cells to this drug. Accordingly, shRNA-mediated down-regulation of P-gp significantly increased the intracellular level of IB-MECA in K562/HHT cells which simultaneously exhibited reduced resistance to this A3AR agonist. In addition, an in vitro enzyme-based assay provided evidence that IB-MECA might serve as a substrate for P-gp. Conclusion:, Our results suggest that P-gp overexpression prevents cells from IB-MECA induced apoptosis despite the A3AR expression. Pro-apoptotic effect of IB-MECA seemed to strongly depend on its intracellular accumulation rather than on its interaction with A3AR. [source] Adenosine A3 receptors in the rat hippocampus: Lack of interaction with A1 receptorsDRUG DEVELOPMENT RESEARCH, Issue 4 2003Luísa V. Lopes Abstract Adenosine acts as a neuromodulator in the hippocampus essentially through activation of inhibitory A1 receptors. Using single-cell PCR analysis, we found that CA1 pyramidal cells coexpress A1 receptor mRNA together with that of another adenosine receptor, the A3 receptor. As occurs for the A1 receptor, Western blot analysis indicated that the A3 receptor is also located in hippocampal nerve terminals. However, activation of A3 receptors with its purportedly selective agonist Cl-IBMECA (0.1,10 µM) failed to affect hippocampal synaptic transmission or to modify the evoked release of glutamate or GABA. Also, blockade of A3 receptors with MRS 1191 (5 µM) failed to affect either hypoxia- or ischemia-induced depression of hippocampal synaptic transmission. Activation of A3 receptors also failed to control A1 receptor function, as Cl-IBMECA (100 nM) did not modify the ability of CPA to displace [3H]DPCPX binding to hippocampal membranes or the A1 receptor-mediated inhibition of hippocampal synaptic transmission. However, ligand binding studies revealed that Cl-IBMECA displaced the binding of an A1 receptor agonist ([3H]R-PIA, Ki=47 nM) or antagonist ([3H]DPCPX, Ki=130 nM), which suggests that A3 receptor ligands also act on native A1 receptors. We believe that A3 receptors are expressed in hippocampal neurons and are located in hippocampal nerve terminals, though their function remains elusive. Drug Dev. Res. 58:428,438, 2003. © 2003 Wiley-Liss, Inc. [source] Agonist-Induced Internalization and Recycling of the Human A3 Adenosine ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 4 2000Resensitization, Role in Receptor Desensitization Abstract: A3 adenosine receptors have been proposed to play an important role in the pathophysiology of cerebral ischemia with a regimen-dependent nature of the therapeutic effects probably related to receptor desensitization and down-regulation. Here we studied the agonist-induced internalization of human A3 adenosine receptors in transfected Chinese hamster ovary cells, and then we evaluated the relationship between internalization and signal desensitization and resensitization. Binding of N6 -(4-amino-3-[125I]iodobenzyl)adenosine-5,- N -methyluronamide to membranes from Chinese hamster ovary cells stably transfected with the human A3 adenosine receptor showed a profile typical of these receptors in other cell lines (KD = 1.3 ± 0.08 nM; Bmax = 400 ± 28 fmol/mg of proteins). The iodinated agonist, bound at 4°C to whole transfected cells, was internalized by increasing the temperature to 37°C with a rate constant of 0.04 ± 0.034 min -1. Agonist-induced internalization of A3 adenosine receptors was directly demonstrated by immunogold electron microscopy, which revealed the localization of these receptors in plasma membranes and intracellular vesicles. Moreover, short-term exposure of these cells to the agonist caused rapid desensitization as tested in adenylyl cyclase assays. Subsequent removal of the agonist led to restoration of the receptor function and recycling of the receptors to the cell surface. The rate constant of receptor recycling was 0.02 ± 0.0017 min -1. Blockade of internalization and recycling demonstrated that internalization did not affect signal desensitization, whereas recycling of internalized receptors was implicated in the signal resensitization. [source] Predictive 3D-Quantitative Structure-Activity Relationship for A1 and A2A Adenosine Receptor LigandsMOLECULAR INFORMATICS, Issue 11-12 2009Olga Yuzlenko Abstract The use of QSAR applications to develop adenosine receptor (AR) antagonists is not so common. A library of all xanthine derivatives, obtained at the Department of Technology and Biotechnology of Drugs, was created. Sixty-three active adenosine A1 receptor ligands and one hundred thirty nine active adenosine A2A receptor ligands were used for 3D-QSAR investigation. The 3D-QSAR equations with a high predictive power in estimating the binding affinity values of potential A1 and A2A ARs ligands were derived. For the first time, hybrid shape-property descriptors were used in 3D-QSAR for xanthine ARs ligands. The obtained models were characterized by a high regression and cross-validation coefficients. Two types of the model validation were tested , dividing the library into the training set for model development and external set for model validation and increasing the number of library components and checking the model by cross-validated regression coefficient. The analysis of the results depicts that for the A1 AR binding activity it is important for ligands to possess R1 -propyl substituents along with the phenyl or benzyl substituents bearing halogen atom and phenethyl moiety. For A2A AR affinity it could be favorable to introduce phenethyl or phenyl substituent connected with the tricyclic ring by the alkoxy chain. The nature of R1 group may not significantly affect the A2A AR affinity. High predictive power of the equations suggests their use for further development of adenosine receptor antagonists within xanthine derivatives. [source] Mechanisms of adenosine-induced cytotoxicity and their clinical and physiological implicationsBIOFACTORS, Issue 1-4 2006Sharmila P. Seetulsingh-Goorah Abstract Extracellular ATP (ATPo) and adenosine are cytotoxic to several cancer cell lines, suggesting their potential use for anticancer therapy. Adenosine causes cytotoxicity, either when added exogenously or when generated from ATPo hydrolysis, via mechanisms which are not mutually exclusive and which involve, adenosine receptor activation, pyrimidine starvation and/or increases in intracellular S-adenosylhomocysteine: S-adenosylmethionine ratio. Given that adenosine also appears to protect against cytotoxicity via mechanisms including immunity against damage by oxygen free radicals, an understanding of the contribution of adenosine to ATPo-induced cytotoxicity is thus crucial, when considering any potential therapeutic use for these compounds. However, such an understanding has been largely hindered by the fact that many studies have not focused enough on the possibility that both ATPo and adenosine may mediate cytotoxicity in the same system. Such studies can benefit from use a range of ATPo concentrations when assessing the contribution of adenosine to ATPo-induced cytotoxicity. Whilst future molecular and pharmacological studies are needed to establish the nature of the cytotoxic adenosine receptor, it is possible that more than just one adenosine receptor type is involved and that the cytotoxic receptor(s) type is more likely to have a low affinity for adenosine. Activation of the adenosine receptor(s) would thus lead to cytotoxicity only at relatively high adenosine concentrations, while lower adenosine concentrations mediate non-cytotoxic physiological effects. [source] In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppressionBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2009Akio Ohta Background and purpose:, The increased levels of extracellular adenosine in inflamed tissues down-regulate activated immune cells via the A2A adenosine receptor. This A2A adenosine receptor-mediated immunosuppression is a disqualifying obstacle in cancer immunotherapy as it protects cancerous tissues from adoptively transferred anti-tumour T cells. The aim of this study was to test whether the negative selection of T cells will produce T cells that are resistant to inhibition by extracellular adenosine. Experimental approach:, Cytotoxic T lymphocytes (CTL) were developed by mixed lymphocyte culture in the presence or absence of the adenosine receptor agonist 5,-N-ethylcarboxamidoadenosine (NECA). The sensitivity of CTL to adenosine analogues was characterized by cAMP induction, interferon-, production and cytotoxicity. Key results:, CTL that could proliferate even in the presence of NECA were less susceptible to inhibition by A2A adenosine receptor agonists, as shown by a much smaller accumulation of cAMP and less inhibition of interferon-, production compared with control CTL. The successful protocol to produce CTL that are both resistant to adenosine-mediated immunosuppression and maintain strong cytotoxicity and interferon-, secretion required NECA to be added only during the expansion stage after the establishment of CTL. In contrast, the priming of resting T cells in the presence of NECA resulted in T cells with impaired effector functions. Conclusions and implications:, Adenosine-resistant effector T cells were successfully obtained by exposure of activated T cells to NECA. These in vitro studies form the basis for future attempts to produce anti-tumour T cells that are more effective in adoptive immunotherapy. [source] Extracellular ATP and adenosine induce cell apoptosis of human hepatoma Li-7A cells via the A3 adenosine receptorBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2003Long T Wen Extracellular ATP is a potent signaling molecule that modulates a myriad of cellular functions through the activation of P2 purinergic receptors and is cytotoxic to a variety of cells at higher concentrations. The mechanism of ATP-elicited cytotoxicity is not fully understood. In this study, we investigated the effect of extracellular ATP on the human hepatoma Li-7A cells. We observed a time- and dose-dependent growth inhibition of Li-7A cells by ATP, which is accompanied by an increase in the active form of caspase-3 as well as increased cleavage of its substrate, poly (ADP-ribose) polymerase. The cytotoxic effect of extracellular ATP was not mediated by the P2X7 receptor, since (1) the effect was not abolished by the P2X7 receptor antagonists oxidized ATP and KN-62, and (2) extracellular ADP, AMP, and adenosine were also cytotoxic. We found that ATP and ADP were degraded to adenosine by Li-7A cells and that treatment of Li-7A cells by adenosine resulted in growth inhibition and caspase-3 activation, indicating that adenosine is the apoptotic agent. Using adenosine receptor agonists and antagonists, as well as inhibitors of adenosine transport and deamination, we showed that the cytotoxic effect of adenosine is specifically mediated by the A3 receptor even though transcripts of A1, A2A, A2B, and a splice variant of the P2X7 receptors were detected in Li-7A cells by RT,PCR. Cytotoxicity caused by exogenous ATP and adenosine was completely abolished by the caspase-3 inhibitor Z-DEVD-FMK, demonstrating the central role of caspase-3 in apoptosis of Li-7A cells. British Journal of Pharmacology (2003) 140, 1009,1018. doi:10.1038/sj.bjp.0705523 [source] Activation of protein kinase B by the A1 -adenosine receptor in DDT1MF-2 cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000Renée Germack In this study the effect of insulin and A1 -adenosine receptor stimulation on protein kinase B (PKB) activation has been investigated in the hamster vas deferens smooth muscle cell line DDT1MF-2. Increases in PKB phosphorylation were determined by Western blotting using an antibody that detects PKB phosphorylation at Ser473. Insulin, a recognized activator of PKB, stimulated a concentration-dependent increase in PKB phosphorylation in DDT1MF-2 cells (EC50 5±1 pM). The selective A1 -adenosine receptor agonist N6 -cyclopentyladenosine (CPA) stimulated time and concentration-dependent increases in PKB phosphorylation in DDT1MF-2 cells (EC50 1.3±0.5 nM). CPA-mediated increases in PKB phosphorylation were antagonized by the A1 -adenosine receptor selective antagonist 1,3-dipropylcyclopentylxanthine (DPCPX) yielding an apparent KD value of 2.3 nM. Pre-treatment of DDT1MF-2 cells with pertussis toxin (PTX, 100 ng ml,1 for 16 h), to block Gi/Go -dependent pathways, abolished CPA (1 ,M) induced phosphorylation of PKB. In contrast, responses to insulin (100 nM) were resistant to PTX pre-treatment. The phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin (IC50 10.3±0.6 nM) and LY 294002 (IC50 10.3±1.2 ,M) attenuated the phosphorylation of PKB elicited by CPA (1 ,M) in a concentration-dependent manner. Wortmannin (30 nM) and LY 294002 (30 ,M) also blocked responses to insulin (100 nM). Removal of extracellular Ca2+ and chelation of intracellular Ca2+ with BAPTA had no significant effect on CPA-induced PKB phosphorylation. Similarly, pretreatment (30 min) with inhibitors of protein kinase C (Ro 31-8220; 10 ,M), tyrosine kinase (genistein; 100 ,M), mitogen-activated protein (MAP) kinase kinase (PD 98059; 50 ,M) and p38 MAPK (SB 203580; 20 ,M) had no significant effect on CPA-induced PKB phosphorylation. In conclusion, these data demonstrate that A1 -adenosine receptor stimulation in DDT1MF-2 cells increases PKB phosphorylation through a PTX and PI-3K-sensitive pathway. British Journal of Pharmacology (2000) 130, 867,874; doi:10.1038/sj.bjp.0703396 [source] Modulation and metamodulation of synapses by adenosineACTA PHYSIOLOGICA, Issue 2 2010J. A. Ribeiro Abstract The presence of adenosine in all nervous system cells (neurones and glia) together with its intensive release following insults makes adenosine as a sort of ,regulator' of synaptic communication, leading to the homeostatic coordination of brain function. Besides the direct actions of adenosine on the neurosecretory mechanisms, to tune neurotransmitter release, adenosine receptors interact with other receptors as well as with transporters as part of its attempt to fine-tune synaptic transmission. This review will focus on examples of the different ways adenosine can use to modulate or metamodulate synapses, in other words, to trigger or brake the action of some neurotransmitters and neuromodulators, to cross-talk with other G protein-coupled receptors, with ionotropic receptors and with receptor kinases as well as with transporters. Most of these interactions occur through A2A receptors, which in spite of their low density in some brain areas, such as the hippocampus, may function as amplifiers of the signalling of other mediators at synapses. [source] Adenosine A1 receptors and vascular reactivityACTA PHYSIOLOGICA, Issue 2 2010Y. Wang Abstract Aim:, Blood pressure is higher in A1 receptor knock-out (A1R,/,) mice than in wild type litter mates (A1R+/+) and we have examined if this could be related to altered vascular functions. Methods:, Contraction of aortic rings and mesenteric arteries were examined. To examine if the adenosine A1 receptor-mediated contraction of aortic muscle was functionally important we examined pulse pressure (PP) and augmentation index (AIX) using a sensor that allows measurements of rapid pressure transients. Results:, Contraction of aortic rings to phenylephrine and relaxation to acetylcholine were similar between genotypes. The non-selective adenosine receptor agonist N -ethyl carboxamido adenosine (NECA) enhanced the contractile response, and this was eliminated in aortas from A1R,/, mice. However, in mesenteric arteries no contractile response was seen and adenosine-mediated relaxation was identical between studied genotypes. A2B adenosine receptors, rather than A2A receptors, may be mainly responsible for the vasorelaxation induced by adenosine analogues in the examined mouse vessels. PP was higher in A1R,/, mice, but variability was unaltered. AIX was not different between genotypes, but the NECA-induced fall was larger in A1R,/, mice. Conclusions:, The role of adenosine A1 receptors in regulating vessel tone differs between blood vessels. Furthermore, contractile effects on isolated vessels cannot explain the blood pressure in A1 knock-out mice. The A1 receptor modulation of blood pressure is therefore mainly related to extravascular factors. [source] Estimation of endogenous adenosine activity at adenosine receptors in guinea-pig ileum using a new pharmacological methodACTA PHYSIOLOGICA, Issue 2 2010K. F. Nilsson Abstract Aim:, Adenosine modulates neurotransmission and in the intestine adenosine is continuously released both from nerves and from smooth muscle. The main effect is modulation of contractile activity by inhibition of neurotransmitter release and by direct smooth muscle relaxation. Estimation of adenosine concentration at the receptors is difficult due to metabolic inactivation. We hypothesized that endogenous adenosine concentrations can be calculated by using adenosine receptor antagonist and agonist and dose ratio (DR) equations. Methods:, Plexus-containing guinea-pig ileum longitudinal smooth muscle preparations were made to contract intermittently by electrical field stimulation in organ baths. Schild plot regressions were constructed with 2-chloroadenosine (agonist) and 8-(p -sulfophenyl)theophylline (8-PST; antagonist). In separate experiments the reversing or enhancing effect of 8-PST and the inhibiting effect of 2-chloroadenosine (CADO) were analysed in the absence or presence of an adenosine uptake inhibitor (dilazep), and nucleoside overflow was measured by HPLC. Results:, Using the obtained DR, baseline adenosine concentration was calculated to 28 nm expressed as CADO activity, which increased dose dependently after addition of 10,6 m dilazep to 150 nm (P < 0.05). HPLC measurements yielded a lower fractional increment (80%) in adenosine during dilazep, than found in the pharmacological determination (440%). Conclusion:, Endogenous adenosine is an important modulator of intestinal neuro-effector activity, operating in the linear part of the dose,response curve. Other adenosine-like agonists might contribute to neuromodulation and the derived formulas can be used to calculate endogenous agonist activity, which is markedly affected by nucleoside uptake inhibition. The method described should be suitable for other endogenous signalling molecules in many biological systems. [source] Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapsesDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2006Linda A. Santschi Abstract Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2,R,3,R)-2-(2,,3,-dicarboxy-cyclopropyl) glycine (DCGIV; 5 ,M), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 ,M), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 ,M) was combined with a cell-permeant PKA inhibitor H-89 (10 ,M), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 ,M), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 ,M), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6 -cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 ,M), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] The pharmacology of cilostazolDIABETES OBESITY & METABOLISM, Issue 2002Karsten Schrör Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 µm). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source] Bioisosterism, enantioselectivity, and molecular modeling of new effective N6 - and/or N(9)-substituted 2-phenyl adenines and 8-aza analogs: Different binding modes to A1 adenosine receptorsDRUG DEVELOPMENT RESEARCH, Issue 2 2001A. Maria Bianucci Abstract Bioisosterism of the adenine and 8-azaadenine nuclei was demonstrated by comparison of A1 adenosine receptor binding affinity of 2-phenyl N6 -substituted adenines and the corresponding 8-azaadenines. Some of these new compounds are very potent A1 adenosine receptor antagonists. This work also describes the synthesis and A1 adenosine receptor binding of the enantiomers of some 2-phenyladenines substituted with a 1-phenylethyl chiral group in N6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2-phenylsubstituted adenines inside A1 adenosine receptors. Theoretical studies, based on an improved A1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52,65, 2001. © 2001 Wiley-Liss, Inc. [source] Functional and molecular evidence of adenosine A2A receptor in coronary arteriolar dilation to adenosineDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Lih Kuo Abstract Adenosine is a potent vasodilator implicated in the regulation of coronary microvascular diameter during metabolic stress. However, the specific adenosine receptors and underlying mechanism responsible for the dilation of coronary microvessels to adenosine remains to be elucidated. Thus, pig subepicardial coronary arterioles (<100 ,m) were isolated, cannulated, and pressurized without flow for in vitro study. All vessels developed basal tone and dilated concentration-dependently to adenosine. Disruption of endothelium and inhibition of nitric oxide (NO) synthase by L-NAME produced identical attenuation of adenosine-induced dilation. KATP channel inhibitor glibenclamide further reduced the dilation of denuded vessels. cAMP antagonist Rp-8-Br-cAMP blocked vasodilation to forskolin, but failed to inhibit vasodilation to adenosine. Coronary dilation to adenosine was blocked by a selective adenosine A2A receptor antagonist ZM241385, but was not altered by an A1 receptor antagonist, DPCPX. Reverse transcription-polymerase chain reaction study revealed that A2A receptor mRNA was expressed in microvessels but not in cardiac myocytes; A1 receptor expression was observed only in cardiac myocytes. These results suggest that adenosine-induced dilation of coronary arterioles is mediated predominantly by A2A receptors. Activation of these receptors elicits vasodilation by endothelial release of NO and by smooth muscle opening of KATP channels in a cAMP-independent manner. Drug Dev. Res. 52:350,356, 2001. © 2001 Wiley-Liss, Inc. [source] Modulation by adenosine of both muscarinic M1 -facilitation and M2 -inhibition of [3H]-acetylcholine release from the rat motor nerve terminalsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Laura Oliveira Abstract The crosstalk between adenosine and muscarinic autoreceptors regulating evoked [3H]-acetylcholine ([3H]-ACh) release was investigated on rat phrenic nerve-hemidiaphragm preparations. Motor nerve terminals possess facilitatory M1 and inhibitory M2 autoreceptors that can be activated by McN-A-343 (1,30 µm) and oxotremorine (0.3,100 µm), respectively. The muscarinic receptor antagonist, dicyclomine (3 nm,10 µm), caused a biphasic (inhibitory/facilitatory) effect, indicating that M1 -facilitation prevails during 5 Hz stimulation trains. Concomitant activation of AF,DX 116-sensitive M2 receptors was partially attenuated, as pretreatment with M1 antagonists, muscarinic toxin 7 (MT-7, 0.1 nm) and pirenzepine (1 nm), significantly enhanced inhibition by oxotremorine. Activation of A2A -adenosine receptors with CGS 21680C (2 nm) (i) potentiated oxotremorine inhibition, and (ii) shifted McN-A-343-induced facilitation into a small inhibitory effect. Conversely, the A1 -receptor agonist, R- N6 -phenylisopropyl adenosine (R-PIA, 100 nm), attenuated the inhibitory effect of oxotremorine, without changing facilitation by McN-A-343. Synergism between A2A and M2 receptors is regulated by a reciprocal interaction with facilitatory M1 receptors, which may be prevented by pirenzepine (1 nm). During 50 Hz-bursts, facilitation (M1) of [3H]-ACh release by McN-A-343 disappeared, while the inhibitory (M2) effect of oxotremorine became predominant. This muscarinic shift results from the interplay with A2A receptors, as it was precluded by the selective A2A receptor antagonist, ZM 241385 (10 nm). In conclusion, when the muscarinic M1 positive feedback loop is fully operative, negative regulation of ACh release is mediated by adenosine A1 receptors. During high frequency bursts, tonic activation of A2A receptors promotes M2 autoinhibition by braking the M1 receptor operated counteraction. [source] Downregulation of protease-activated receptor-1 in human lung fibroblasts is specifically mediated by the prostaglandin E2 receptor EP2 through cAMP elevation and protein kinase AFEBS JOURNAL, Issue 14 2008Elena Sokolova Many cellular functions of lung fibroblasts are controlled by protease-activated receptors (PARs). In fibrotic diseases, PAR-1 plays a major role in controlling fibroproliferative and inflammatory responses. Therefore, in these diseases, regulation of PAR-1 expression plays an important role. Using the selective prostaglandin EP2 receptor agonist butaprost and cAMP-elevating agents, we show here that prostaglandin (PG)E2, via the prostanoid receptor EP2 and subsequent cAMP elevation, downregulates mRNA and protein levels of PAR-1 in human lung fibroblasts. Under these conditions, the functional response of PAR-1 in fibroblasts is reduced. These effects are specific for PGE2. Activation of other receptors coupled to cAMP elevation, such as ,-adrenergic and adenosine receptors, does not reproduce the effects of PGE2. PGE2 -mediated downregulation of PAR-1 depends mainly on protein kinase A activity, but does not depend on another cAMP effector, the exchange protein activated by cAMP. PGE2 -induced reduction of PAR-1 level is not due to a decrease of PAR-1 mRNA stability, but rather to transcriptional regulation. The present results provide further insights into the therapeutic potential of PGE2 to specifically control fibroblast function in fibrotic diseases. [source] The type 1 equilibrative nucleoside transporter regulates anxiety-like behavior in miceGENES, BRAIN AND BEHAVIOR, Issue 8 2007J. Chen Activation of adenosine receptors in the brain reduces anxiety-like behavior in animals and humans. Because nucleoside transporters regulate adenosine levels, we used mice lacking the type 1 equilibrative nucleoside transporter (ENT1) to investigate whether ENT1 contributes to anxiety-like behavior. The ENT1 null mice spent more time in the center of an open field compared with wild-type littermates. In the elevated plus maze, ENT1 null mice entered more frequently into and spent more time exploring the open arms. The ENT1 null mice also spent more time exploring the light side of a light,dark box compared with wild-type mice. Microinjection of an ENT1-specific antagonist, nitrobenzylthioinosine (nitrobenzylmercaptopurine riboside), into the amygdala of C57BL/6J mice reduced anxiety-like behavior in the open field and elevated plus maze. These findings show that amygdala ENT1 modulates anxiety-like behavior. The ENT1 may be a drug target for the treatment of anxiety disorders. [source] The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?HUMAN BRAIN MAPPING, Issue 10 2009Merideth A. Addicott Abstract Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use. Hum Brain Mapp 2009. © 2009 Wiley-Liss, Inc. [source] Regulation of A2A adenosine receptor expression and functioning following permanent focal ischemia in rat brainJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Maria L. Trincavelli Abstract Ischemia, through modulation of adenosine receptors (ARs), may influence adenosine-mediated-cellular responses. In the present study, we investigated the modulation of rat A2A receptor expression and functioning, in rat cerebral cortex and striatum, following in vivo focal ischemia (24 h). In cortex, middle cerebral artery occlusion did not induce any alterations in A2A receptor binding and functioning. On the contrary, in striatum, a significant decrease in A2A ligand affinity, associated with an increase in receptor density, were detected. In striatum, ischemia also induced a significant reduction both in G protein pool and in A2A receptor-G protein coupling. On the contrary, A2A receptor functional responsiveness, measured as stimulation of adenylyl cyclise, was not affected by ischemia, suggesting receptor up-regulation may represent a compensatory mechanism to maintain receptor functioning during cerebral damage. Immunohistochemical study showed that following 24 h middle cerebral artery occlusion, A2A ARs were definitely expressed both on neurons and activated microglia in ischemic striatum and cortex, but were not detected on astrocytes. In the non-ischemic hemisphere and in sham-operated rats A2A ARs were barely detected. Modifications of ARs may play a significant role in determining adenosine effects during ischemia and therefore should be taken into account when evaluating time-dependent protective effects of specific A2A active compounds. [source] | ||||||||||||||||