Barbiturates Are Selective Antagonists at A<sub>1</sub> Adenosine Receptors

Lohse, Martin J.; Klotz, Karl‐Norbert; Jakobs, Karl H.; Schwabe, Ulrich

doi:10.1111/j.1471-4159.1985.tb10532.x

Cited by 60 publications

(25 citation statements)

References 43 publications

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“…The interaction may be greatly surface increased V max substantially, but EC 50 did not change (10). Similarly, if the receptor number was reduced by 90% through a covalent modification, the V max of adenylyl cyclase activation declined, but the EC 50 was only marginally affected (43). These considerations further support the conjecture that the restricted collision coupling model is a feature of the A 2A receptor proper, which is observed regardless of the cellular background.…”

Section: Discussionsupporting

confidence: 70%

Restricted Collision Coupling of the A2A Receptor Revisited

Charalambous

Gsandtner

Keuerleber

et al. 2008

Journal of Biological Chemistry

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The A 2A -adenosine receptor is a prototypical G s protein-coupled receptor but stimulates MAPK/ERK in a G s -independent way. The A 2A receptor has long been known to undergo restricted collision coupling with G s ; the mechanistic basis for this mode of coupling has remained elusive. Here we visualized agonist-induced changes in mobility of the yellow fluorescent protein-tagged receptor by fluorescence recovery after photobleaching microscopy. Stimulation with a specific A 2A receptor agonist did not affect receptor mobility. In contrast, stimulation with dopamine decreased the mobility of the D 2 receptor. When coexpressed in the same cell, the A 2A receptor precluded the agonist-induced change in D 2 receptor mobility. Thus, the A 2A receptor did not only undergo restricted collision coupling, but it also restricted the mobility of the D 2 receptor. Restricted mobility was not due to tethering to the actin cytoskeleton but was, in part, related to the cholesterol content of the membrane. Depletion of cholesterol increased receptor mobility but blunted activation of adenylyl cyclase, which was accounted for by impaired formation of the ternary complex of agonist, receptor, and G protein. These observations support the conclusion that the A 2A receptor engages G s and thus signals to adenylyl cyclase in cholesterol-rich domains of the membrane. In contrast, stimulation of MAPK by the A 2A receptor was not impaired. These findings are consistent with a model where the recruitment of these two pathways occurs in physically segregated membrane microdomains. Thus, the A 2A receptor is the first example of a G protein-coupled receptor documented to select signaling pathways in a manner dependent on the lipid microenvironment of the membrane.In the fluid mosaic model, the lipid bilayer is an isotropic milieu, in which membrane-embedded proteins diffuse in two dimensions and thus collide at random with each other (1). When applied to G protein-coupled receptors, the model predicts that G protein-coupled receptors move in a random walk, and, upon activation, this allows them to engage their cognate G proteins. This "collision coupling" mode of activation was validated in studies using the ␤-adrenergic receptor and its coupling to the effector enzyme adenylyl cyclase in turkey erythrocytes (2). However, experiments with the A 2 -adenosine receptor in turkey erythrocytes revealed kinetic properties of adenylyl cyclase activation that were incompatible with the collision coupling model. The results indicated a tight coupling of the adenosine receptor to G␣ s (3, 4); the term "restricted collision coupling" was coined to account for this altered mode of coupling. Restricted collision is not a feature unique to the avian A 2 -adenosine receptor, because it was also documented for the human A 2A receptor in platelet membranes (5). In addition, the A 2A -adenosine receptor has the unusual feature of forming a tight complex with G s , which persists in detergent solution, which is resistant to guanine nucleotides and which re...

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Section: Discussionsupporting

confidence: 70%

Restricted Collision Coupling of the A2A Receptor Revisited

Charalambous

Gsandtner

Keuerleber

et al. 2008

Journal of Biological Chemistry

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“…However, such a model is incompatible with several published reports. Notably, only about 20% of the A 2A R is actually coupled to G-protein in platelets (56) and striatum (14,57). Furthermore, in these tissues, the G-protein appears to control the rate of adenylyl cyclase activation (58).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum

Schwindinger

Mihalcik

Giger

et al. 2010

Journal of Biological Chemistry

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The adenosine A 2A receptor (A 2A R) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein ␣ olf subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the ␤␥ dimer also performs an active role in this signal transduction process. In principal, sixty distinct ␤␥ dimers could arise from combinatorial association of the five known ␤ and 12 ␥ subunit genes. However, key questions regarding which ␤␥ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein ␥ 7 subtype. Revealing a potentially new signaling paradigm, we show that the level of the ␥ 7 protein controls the hierarchial assembly of a specific G-protein ␣ olf ␤ 2 ␥ 7 heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A 2A R activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein ␥ 7 subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A 2A R G-protein ␣ olf ␤ 2 ␥ 7 interface as a possible therapeutic target for Parkinson disease.G-protein-coupled receptors represent the single largest family of target proteins for drug development. Their actions require the participation of heterotrimeric guanine nucleotide binding proteins (G-proteins) whose roles in these diverse signaling pathways may be determined by their specific ␣␤␥ subunit combinations. The existence of 16 ␣, 5 ␤, and 12 ␥ subtypes creates the potential to generate a large number of distinct G-protein ␣␤␥ heterotrimers (1, 2). Although their biochemical properties have been well studied (3, 4), key questions regarding which G-protein ␣␤␥ heterotrimers actually exist in vivo and determining whether they perform specific signaling roles and biological functions remain to be answered. To address these questions, a gene-targeting approach has been used to delete the various ␣ subunit genes in mice, leading to the identification of physiological functions for most of them (5). By contrast, little attention has focused on the ␤ and ␥ subunit genes. In particular, several features of the ␥ subunit genes suggest they may perform heterogeneous functions in vivo. Analogous to their ␣ partners, the various ␥ subtypes show substantial structural diversity and exhibit pleiotropic patterns of expression (2). Accordingly, we have undertaken a gene targeting approach to systematically ablate the individual ␥ subtypes in mice (6, 7), with the ultimate goal of elucidating their biological functions.Our recent work has demonstrated that knock-out of Gng7, encoding the ␥ 7 subtype, produces a behavioral phenotype result...

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“…Etazolate also is a potent phosphodiesterase inhibitor [38]. It should be noted that barbiturates represent another class of compounds that enhance diazepam binding to the GABA-receptor-channel complex [39] and have similar potencies at such complexes and as antagonists at adenosine receptors [28,29], suggesting again structural analogies between certain regulatory sites on the GABA-receptor-channel complex and antagonist sites on adenosine receptors. A wide variety of purines and xanthines inhibit binding of diazepam to the GABA-receptor-channel complex [40] and one N 6 -substituted adenosine (EMD 28422) increases the apparent number of diazepam binding sites in brain membranes [41].…”

Section: Pyrazolopyridinesmentioning

confidence: 99%

“…Other classes of heterocyclic compounds exhibit antagonist activity at adenosine receptors. These include: 9-methyladenines [10,14], various pyrazolopyridines (etazolate, cartazolate, tracazolate) [15][16][17][18], various pyrazolopyrimidines [19,20], imidazopyrazines [21], a phenyl-substituted pyrazoloquinoline (CGS 8216) [22,23], a furyl-sub-stituted triazoloquinazoline (CGS 15943a) [24], a triazolopyridazine (CL218872) [15], various mesoionic analogs of xanthines [25], pteridin-2,4-diones (lumazine) and benzopteridin-2,4-diones [10,26], β-carbolines [15,27], barbiturates [28,29] and dibenzazepines (carbamazepine) [30][31][32][33]. A phenylaminoimidazoline, clonidine, has been reported to antagonize adenosine responses in physiological experiments [34].…”

Section: Introductionmentioning

confidence: 99%

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

Daly

Hong

Padgett

et al. 1988

Biochemical Pharmacology

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A variety of non-xanthine heterocycles were found to be antagonists of binding of [ 3 H]phenylisopropyladenosine to rat brain A 1 -adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxarnidoadenosine with A 2 -adenosine receptors in human platelet and rat pheochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A 1 -and A 2 -adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N 6 -substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A 1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A 1 and A 2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A 1 -and A 2 -adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and β-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak noncompetitive adenosine antagonist.Xanthines, such as theophylline, caffeine and various 8-aryl-1,3-dialkylxanthines, have been widely used as antagonists of A 1 and A 2 -adenosine receptors [1]. The 8-aryl-1,3-dialkylxanthines are very potent at both subclasses of adenosine receptors [2][3][4][5][6][7][8][9][10][11]. Certain 8-aryl-1,3-dipropylxanthines exhibit selectivity for A 1 receptors [4,8,9] and certain caffeine analogs exhibit some selectivity for A 2 receptors [12,13]. Other classes of heterocyclic compounds exhibit antagonist activity at adenosine receptors. These include: 9-methyladenines [10,14], various pyrazolopyridines (etazolate, cartazolate, tracazolate) [15][16][17][18], various pyrazolopyrimidines [19,20], imidazopyrazines [21], a phenyl-substituted pyrazoloquinoline (CGS 8216) [22,23], a furyl-sub-stituted triazoloquinazoline (CGS 15943a) [24], a triazolopyridazine (CL218872) [15], various mesoionic analogs of xanthines [25], pteridin-2,4-diones (lumazine) and benzopteridin-2,4-diones [10,26], β-carbolines [15,27], barbiturates [28,29] and dibenzazepines (carbamazepine) [30][31][32][33]. A phenylaminoimidazoline, clonidine, has been reported to antagonize adenosine responses in physiological experiments [34].The non-xanthine adenosine antagonists have been largely neglected in behavioral and physiological studies, and little is known of structure-activity relationships within such METHODS MaterialsThe sources from which we obtained our mat...

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Barbiturates Are Selective Antagonists at A₁ Adenosine Receptors

Cited by 60 publications

References 43 publications

Restricted Collision Coupling of the A2A Receptor Revisited

Restricted Collision Coupling of the A2A Receptor Revisited

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

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Barbiturates Are Selective Antagonists at A1 Adenosine Receptors

Cited by 60 publications

References 43 publications

Restricted Collision Coupling of the A2A Receptor Revisited

Restricted Collision Coupling of the A2A Receptor Revisited

Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

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Barbiturates Are Selective Antagonists at A₁ Adenosine Receptors