Interacting selectively and non-covalently with alpha-actinin, one of a family of proteins that cross-link F-actin as antiparallel homodimers. Alpha-actinin has a molecular mass of 93-103 KDa; at the N-terminus there are two calponin homology domains, at the C-terminus there are two EF-hands. These two domains are connected by the rod domain. This domain is formed by triple-helical spectrin repeats.
Many membrane proteins incur a folding problem during biosynthesis; only a fraction thereof is exported from the endoplasmic reticulum (ER), because quality control is stringent. This is also true for G protein-coupled receptors. Here, we identify the deubiquitinating enzyme Usp4 as an interaction partner of the A2a adenosine receptor, a Gs-coupled receptor. Usp4 binds to the carboxyl terminus of the A2A receptor and allows for its accumulation as deubiquinated protein. This relaxes ER quality control and enhances cell surface expression of functionally active receptor. The effect of Usp4 on the A2A receptor was specific because 1) it was not seen in C-terminally truncated versions of the receptor; 2) it was not mimicked by Usp14, another member of the ubiquitin-specific protease family; and 3) it was not seen with the metabotropic glutamate receptor-5, another G protein-coupled receptor with a high propensity for intracellular retention. These observations show that deubiquinating enzymes can regulate quality control in the ER.
Combining with adenosine and transmitting the signal across the membrane by activating an associated G-protein; promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
The Ca(2+)-binding protein calmodulin (CaM) has been shown to bind directly to cytoplasmic domains of some G protein-coupled receptors, including the dopamine D(2) receptor. CaM binds to the N-terminal portion of the long third intracellular loop of the D(2) receptor, within an Arg-rich epitope that is also involved in the binding to G(i/o) proteins and to the adenosine A(2A) receptor, with the formation of A(2A)-D(2) receptor heteromers. In the present work, by using proteomics and bioluminescence resonance energy transfer (BRET) techniques, we provide evidence for the binding of CaM to the A(2A) receptor. By using BRET and sequential resonance energy transfer techniques, evidence was obtained for CaM-A(2A)-D(2) receptor oligomerization. BRET competition experiments indicated that, in the A(2A)-D(2) receptor heteromer, CaM binds preferentially to a proximal C terminus epitope of the A(2A) receptor. Furthermore, Ca(2+) was found to induce conformational changes in the CaM-A(2A)-D(2) receptor oligomer and to selectively modulate A(2A) and D(2) receptor-mediated MAPK signaling in the A(2A)-D(2) receptor heteromer. These results may have implications for basal ganglia disorders, since A(2A)-D(2) receptor heteromers are being considered as a target for anti-parkinsonian agents.
Evidence
2:
Inferred from Physical InteractionIntAct
Heptaspanning membrane also known as G protein-coupled receptors (GPCR) do interact with a variety of intracellular proteins whose function is regulate receptor traffic and/or signaling. Using a yeast two-hybrid screen, NECAB2, a neuronal calcium binding protein, was identified as a binding partner for the adenosine A(2A) receptor (A(2A)R) interacting with its C-terminal domain. Co-localization, co-immunoprecipitation and pull-down experiments showed a close and specific interaction between A(2A)R and NECAB2 in both transfected HEK-293 cells and also in rat striatum. Immunoelectron microscopy detection of NECAB2 and A(2A)R in the rat striatopallidal structures indicated that both proteins are co-distributed in the same glutamatergic nerve terminals. The interaction of NECAB2 with A(2A)R modulated the cell surface expression, the ligand-dependent internalization and the receptor-mediated activation of the MAPK pathway. Overall, these results show that A(2A)R interacts with NECAB2 in striatal neurones co-expressing the two proteins and that the interaction is relevant for A(2A)R function.
Evidence
3:
Inferred from Physical InteractionUniProtKB
The ubiquitin pathway is involved in the proteolytic turnover of many short-lived cellular regulatory proteins. Since selective degradation of substrates of this system requires the covalent attachment of a polyubiquitin chain to the substrates, degradation could be counteracted by de-ubiquitinating enzymes (or isopeptidases) which selectively remove the polyubiquitin chain. Unp is a human isopeptidase with still poorly understood biological functions. Here, we show that cellular Unp specifically interacts with the retinoblastoma gene product (pRb).
Evidence
4:
Inferred from Physical InteractionIntAct
The physiological meaning of the coexpression of adenosine A2A receptors and group I metabotropic glutamate receptors in gamma- aminobutyric acid (GABA)ergic striatal neurons is intriguing. Here we provide in vitro and in vivo evidence for a synergism between adenosine and glutamate based on subtype 5 metabotropic glutamate (mGluR5) and adenosine A2A (A2AR) receptor/receptor interactions. Colocalization of A2AR and mGluR5 at the membrane level was demonstrated in nonpermeabilized human embryonic kidney (HEK)-293 cells transiently cotransfected with both receptors by confocal laser microscopy. Complexes containing A2AR and mGluR5 were demonstrated by Western blotting of immunoprecipitates of either Flag-A2AR or hemagglutinin-mGluR5 in membrane preparations from cotransfected HEK-293 cells and of native A2AR and mGluR5 in rat striatal membrane preparations. In cotransfected HEK-293 cells a synergistic effect on extracellular signal-regulated kinase 1/2 phosphorylation and c-fos expression was demonstrated upon A2AR/mGluR5 costimulation. No synergistic effect was observed at the second messenger level (cAMP accumulation and intracellular calcium mobilization). Accordingly, a synergistic effect on c-fos expression in striatal sections and on counteracting phencyclidine-induced motor activation was also demonstrated after the central coadministration of A2AR and mGluR5 agonists to rats with intact dopaminergic innervation. The results suggest that a functional mGluR5/A2AR interaction is required to overcome the well-known strong tonic inhibitory effect of dopamine on striatal adenosine A2AR function.
Evidence
5:
Inferred from Physical InteractionIntAct
The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
Evidence
6:
Inferred from Physical InteractionIntAct
The A2A adenosine receptor is a prototypical G(s)-coupled receptor, but it also signals, e.g. to mitogen-activated protein (MAP) kinase, via a pathway that is independent of heterotrimeric G proteins. Truncation of the carboxyl terminus affects the strength of the signal through these alternative pathways. In a yeast two-hybrid interaction hunt, we screened a human brain library for proteins that bound to the juxtamembrane portion of the carboxyl terminus of the A2A receptor. This approach identified ARNO/cytohesin-2, a nucleotide exchange factor for the small (monomeric) G proteins of the Arf (ADP-ribosylation factor) family, as a potential interaction partner. We confirmed a direct interaction by mutual pull down (of fusion proteins expressed in bacteria) and by immunoprecipitation of the proteins expressed in mammalian cells. To circumvent the long term toxicity associated with overexpression of ARNO/cytohesin-2, we created stable cell lines that stably expressed the A2A receptor and where ARNO/cytohesin-2 or the dominant negative version E156K-ARNO/cytohesin-2 was inducible by mifepristone. Cyclic AMP accumulation induced by an A2A-specific agonist was neither altered by ARNO/cytohesin-2 nor by the dominant negative version. This was also true for agonist-induced desensitization. In contrast, expression of dominant negative E156K-ARNO/cytohesin-2 and of dominant negative T27N-Arf6 abrogated the sustained phase of MAP kinase stimulation induced by the A2A receptor. We therefore conclude that ARNO/cytohesin-2 is required to support the alternative, heterotrimeric G protein-independent, signaling pathway of A2A receptor, which is stimulation of MAP kinase.
Evidence
7:
Inferred from Physical InteractionIntAct
Many membrane proteins incur a folding problem during biosynthesis; only a fraction thereof is exported from the endoplasmic reticulum (ER), because quality control is stringent. This is also true for G protein-coupled receptors. Here, we identify the deubiquitinating enzyme Usp4 as an interaction partner of the A2a adenosine receptor, a Gs-coupled receptor. Usp4 binds to the carboxyl terminus of the A2A receptor and allows for its accumulation as deubiquinated protein. This relaxes ER quality control and enhances cell surface expression of functionally active receptor. The effect of Usp4 on the A2A receptor was specific because 1) it was not seen in C-terminally truncated versions of the receptor; 2) it was not mimicked by Usp14, another member of the ubiquitin-specific protease family; and 3) it was not seen with the metabotropic glutamate receptor-5, another G protein-coupled receptor with a high propensity for intracellular retention. These observations show that deubiquinating enzymes can regulate quality control in the ER.
The series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand, where the pathway proceeds through activation of adenylyl cyclase activity and a subsequent increase in the concentration of cyclic AMP (cAMP).
The series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand, where the pathway proceeds through activation or inhibition of adenylyl cyclase activity and a subsequent change in the concentration of cyclic AMP (cAMP).
BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.
A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathways) which typically lead to rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. The process ends when the cell has died. The process is divided into a signaling pathway phase, and an execution phase, which is triggered by the former.
Biochem. J. 304 ( Pt 3), 877-885 (1994)[PubMed:7818494]
Incubation of human thymocytes with an optimum concentration of adenosine and its receptor site agonist, 2-chloroadenosine, induced increases in intracellular cyclic AMP (cAMP) (from a resting 0.6 +/- 0.1 to 4.1 +/- 0.2 pmol/10(7) cells within 5 min) and Ca2+ (from the resting 85 +/- 7 nM to a peak of 210 +/- 25 nM) levels and resulted in internucleosomal DNA fragmentation and cell death (apoptosis). Other adenosine analogues were also effective at inducing DNA fragmentation, the order of potency being 2-p-(carboxyethylphenylethylamino)-5'-carboxyamidoadenosine < 5'-(N-ethylcarboxamide)adenosine < or = cyclopentyladenosine < 2-chloroadenosine (2-CA). 2-CA treatment (with an optimum concentration of 40 microM) selectively depleted a thymocyte subpopulation (15-20% of the total cells) which expressed higher levels of the CD3 molecule and which was found mainly in the CD4+CD8+ double positive immature thymocyte population. DNA fragmentation was prevented by the addition of actinomycin D or cycloheximide to the thymocyte suspension, indicating that this process required both mRNA and protein synthesis. Endonuclease activation and cell killing were dependent on an early, sustained increase in cytosolic Ca2+ concentration, most of which was of extracellular origin and was a result of an adenosine-induced inositol trisphosphate release. Other agents known to elevate intracellular cAMP levels by different mechanisms failed to induce similar DNA fragmentation, but enhanced the effect of adenosine. This suggested a supporting role for cAMP in adenosine-induced DNA fragmentation. Phorbol dibutyrate, a protein kinase. C activator, previously shown to inhibit Ca(2+)-dependent DNA fragmentation and cell killing in human thymocytes [McConkey, Hartzell, Jondal and Orrenius (1989) J. Biol. Chem. 264, 13399-13402], at 60 ng/ml concentration also prevented adenosine-induced DNA fragmentation when added prior to adenosine. This suggested a complex cross-talk between the adenosine-triggered signal transduction cascade and the activation state of protein kinase C in regulating apoptosis of human thymocytes.
Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.
The sequential process in which the multiple coagulation factors of the blood interact, ultimately resulting in the formation of an insoluble fibrin clot; it may be divided into three stages: stage 1, the formation of intrinsic and extrinsic prothrombin converting principle; stage 2, the formation of thrombin; stage 3, the formation of stable fibrin polymers.
BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.
BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.
Biochem. J. 304 ( Pt 3), 877-885 (1994)[PubMed:7818494]
Incubation of human thymocytes with an optimum concentration of adenosine and its receptor site agonist, 2-chloroadenosine, induced increases in intracellular cyclic AMP (cAMP) (from a resting 0.6 +/- 0.1 to 4.1 +/- 0.2 pmol/10(7) cells within 5 min) and Ca2+ (from the resting 85 +/- 7 nM to a peak of 210 +/- 25 nM) levels and resulted in internucleosomal DNA fragmentation and cell death (apoptosis). Other adenosine analogues were also effective at inducing DNA fragmentation, the order of potency being 2-p-(carboxyethylphenylethylamino)-5'-carboxyamidoadenosine < 5'-(N-ethylcarboxamide)adenosine < or = cyclopentyladenosine < 2-chloroadenosine (2-CA). 2-CA treatment (with an optimum concentration of 40 microM) selectively depleted a thymocyte subpopulation (15-20% of the total cells) which expressed higher levels of the CD3 molecule and which was found mainly in the CD4+CD8+ double positive immature thymocyte population. DNA fragmentation was prevented by the addition of actinomycin D or cycloheximide to the thymocyte suspension, indicating that this process required both mRNA and protein synthesis. Endonuclease activation and cell killing were dependent on an early, sustained increase in cytosolic Ca2+ concentration, most of which was of extracellular origin and was a result of an adenosine-induced inositol trisphosphate release. Other agents known to elevate intracellular cAMP levels by different mechanisms failed to induce similar DNA fragmentation, but enhanced the effect of adenosine. This suggested a supporting role for cAMP in adenosine-induced DNA fragmentation. Phorbol dibutyrate, a protein kinase. C activator, previously shown to inhibit Ca(2+)-dependent DNA fragmentation and cell killing in human thymocytes [McConkey, Hartzell, Jondal and Orrenius (1989) J. Biol. Chem. 264, 13399-13402], at 60 ng/ml concentration also prevented adenosine-induced DNA fragmentation when added prior to adenosine. This suggested a complex cross-talk between the adenosine-triggered signal transduction cascade and the activation state of protein kinase C in regulating apoptosis of human thymocytes.
Signaling through A2A adenosine receptors (A2AR) regulates T lymphocyte expansion and modulates T cell receptor (TCR)-mediated effector functions in vitro. To understand the role of A2ARs in the regulation of immune response, we investigated the expression levels of this receptor in different functional lymphocyte subsets. Monoclonal anti-A2AR antibody was used to develop a flow cytometric assay to quantify the expression A2ARs on lymphocytes. We report that detectable levels of expression of A2ARs are much higher among T cells than B cells. More CD4(+) than CD8(+) T cells express A2ARs, but activation of T cells increases A2AR expression, predominantly in CD8(+) T cells. No significant differences were found in the proportion of A2AR+ cells between CD8(low) and CD8(high) T cells or between TCR/CD3(low) and TCR/CD3(high) T cells. Studies of T helper cell subsets (TH1 and TH2) reveal that lymphokine-producing cells are much more likely to express A2ARs than are cells that do not produce lymphokines. These results suggest that A2ARs are variably expressed on T cell subsets and may regulate cytokine production in activated T lymphocytes.
The process whose specific outcome is the progression of the central nervous system over time, from its formation to the mature structure. The central nervous system is the core nervous system that serves an integrating and coordinating function. In vertebrates it consists of the brain, spinal cord and spinal nerves. In those invertebrates with a central nervous system it typically consists of a brain, cerebral ganglia and a nerve cord.
In a previous study (Comings DE et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196) we examined the role of 20 dopamine, serotonin and norepinephrine genes in attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), using a multivariate analysis of associations (MAA) technique. We have now brought the total number of genes examined to 42 by adding an additional 22 candidate genes. These results indicate that even with the inclusion of these additional genes the noradrenergic genes still played a greater role in ADHD than any other group. Six other neurotransmitter genes were included in the regression equation - cholinergic, nicotinic, alpha 4 receptor (CHNRA4), adenosine A2A receptor (ADOA2A), nitric oxide synthase (NOS3), NMDAR1, GRIN2B, and GABRB3. In contrast to ADHD and ODD, CD preferentially utilized hormone and neuropeptide genes These included CCK, CYP19 (aromatase cytochrome P-450), ESR1, and INS (p = 0.005). This is consistent with our prior studies indicating a role of the androgen receptor (AR) gene in a range of externalizing behavors. We propose that the MAA technique, by focusing on the additive effect of multiple genes and on the cummulative effect of functionally related groups of genes, provides a powerful approach to the dissection of the genetic basis of polygenic disorders.
The specific actions or reactions of an organism relating to the intake of food, any substance (usually solid) that can be metabolized by an organism to give energy and build tissue.
The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
Using monoclonal anti-adenosine A1 receptor antibodies that bind the A1 receptor ligand binding site, we demonstrate that A1 receptors are expressed on cultured monocytes and rheumatoid synovial fluid mononuclear phagocytes. This finding is associated with the acquisition of reactivity with selective adenosine A1 receptor agonists and is temporally coordinated with the induction of adenosine A2 receptors on cultured monocytes. In a rapid, concentration-dependent fashion, these two distinct adenosine receptors modulate Fc gamma receptor-mediated phagocytosis, a response critical to the pathogenesis of immune complex diseases. Occupancy of A1 receptors by N6-cyclopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent stimulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fc gamma receptor-mediated phagocytosis is a consequence of preferential augmentation of Fc gamma RI function, suggesting distinct mechanisms for receptor-effector coupling of Fc gamma receptor families. In contrast, ligation of A2 receptors by A2-specific agonists decreases Fc gamma receptor-mediated phagocytosis in cultured monocytes. The opposing effects of adenosine A1 and A2 receptors allow for a concentration-dependent feed-back loop that responds more rapidly than effects elicited by other endogenous modulators. Low concentrations of adenosine are proinflammatory providing enhanced Fc gamma receptor function via A1 receptors, whereas higher concentrations that can occur with tissue damage are anti-inflammatory providing inhibition via A2 receptors. This rapid and potent modulation of Fc gamma receptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.
The specific movement from place to place of an organism in response to external or internal stimuli. Locomotion of a whole organism in a manner dependent upon some combination of that organism's internal state and external conditions.
Any process that stops, prevents or reduces the rate or extent of cell proliferation.
IEAOrtholog Compara
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic processdefinition[GO:0043154]‹silver
Any process that stops, prevents, or reduces the frequency, rate or extent of a cysteine-type endopeptidase activity involved in the apoptotic process.
The process in which the anatomical structures of a neuron projection are generated and organized. A neuron projection is any process extending from a neural cell, such as axons or dendrites.
An endocytosis process that results in the engulfment of external particulate material by phagocytes. The particles are initially contained within phagocytic vacuoles (phagosomes), which then fuse with primary lysosomes to effect digestion of the particles.
Using monoclonal anti-adenosine A1 receptor antibodies that bind the A1 receptor ligand binding site, we demonstrate that A1 receptors are expressed on cultured monocytes and rheumatoid synovial fluid mononuclear phagocytes. This finding is associated with the acquisition of reactivity with selective adenosine A1 receptor agonists and is temporally coordinated with the induction of adenosine A2 receptors on cultured monocytes. In a rapid, concentration-dependent fashion, these two distinct adenosine receptors modulate Fc gamma receptor-mediated phagocytosis, a response critical to the pathogenesis of immune complex diseases. Occupancy of A1 receptors by N6-cyclopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent stimulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fc gamma receptor-mediated phagocytosis is a consequence of preferential augmentation of Fc gamma RI function, suggesting distinct mechanisms for receptor-effector coupling of Fc gamma receptor families. In contrast, ligation of A2 receptors by A2-specific agonists decreases Fc gamma receptor-mediated phagocytosis in cultured monocytes. The opposing effects of adenosine A1 and A2 receptors allow for a concentration-dependent feed-back loop that responds more rapidly than effects elicited by other endogenous modulators. Low concentrations of adenosine are proinflammatory providing enhanced Fc gamma receptor function via A1 receptors, whereas higher concentrations that can occur with tissue damage are anti-inflammatory providing inhibition via A2 receptors. This rapid and potent modulation of Fc gamma receptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.
Any process that activates, maintains or increases the frequency, rate or extent of GABAergic synaptic transmission, the process of communication from a neuron to another neuron across a synapse using the neurotransmitter gamma-aminobutyric acid (GABA).
IEAOrtholog Compara
Positive regulation of synaptic transmission, glutamatergicdefinition[GO:0051968]‹silver
Any process that activates, maintains or increases the frequency, rate or extent of glutamatergic synaptic transmission, the process of communication from a neuron to another neuron across a synapse using the neurotransmitter glutamate.
The process in which a startle magnitude is reduced when the startling stimulus is preceded by a low-intensity prepulse.
IEAOrtholog Compara
Protein kinase C-activating G-protein coupled receptor signaling pathwaydefinition[GO:0007205]‹silver
The series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand, where the pathway proceeds with activation of protein kinase C (PKC). PKC is activated by second messengers including diacylglycerol (DAG).
Any process that modulates the frequency, rate or extent of the directed movement of calcium ions into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.
Any process that modulates the establishment or extent of the excitatory postsynaptic potential (EPSP) which is a temporary increase in postsynaptic potential due to the flow of positively charged ions into the postsynaptic cell. The flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC) and makes it easier for the neuron to fire an action potential.
Any process that modulates the establishment or extent of the inhibitory postsynaptic potential (IPSP) which is a temporary decrease in postsynaptic membrane potential due to the flow of negatively charged ions into the postsynaptic cell. The flow of ions that causes an IPSP is an inhibitory postsynaptic current (IPSC) and makes it more difficult for the neuron to fire an action potential.
Any process that modulates the establishment or extent of the mitochondrial membrane potential, the electric potential existing across the mitochondrial membrane arising from charges in the membrane itself and from the charges present in the media on either side of the membrane.
A process that modulates synaptic plasticity, the ability of synapses to change as circumstances require. They may alter function, such as increasing or decreasing their sensitivity, or they may increase or decrease in actual numbers.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an amphetamine stimulus. Amphetamines consist of a group of compounds related to alpha-methylphenethylamine.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a caffeine stimulus. Caffeine is an alkaloid found in numerous plant species, where it acts as a natural pesticide that paralyzes and kills certain insects feeding upon them.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a drug stimulus. A drug is a substance used in the diagnosis, treatment or prevention of a disease.
The series of events required for an organism to receive a sensory stimulus, convert it to a molecular signal, and recognize and characterize the signal. This is a neurological process.
Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.
Receptors which transduce extracellular signals across the cell membrane. At the external side they receive a ligand (a photon in case of opsins), and at the cytosolic side they activate a guanine nucleotide-binding (G) protein. These receptors are hydrophobic proteins that cross the membrane seven times.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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