l-DOPA-treatment in primates disrupts the expression of A2A adenosine–CB1 cannabinoid–D2 dopamine receptor heteromers in the caudate nucleus

Bonaventura, Jordi; Rico, Alberto J.; Moreno, Estefanía; Sierra, Salvador; Sanchéz, M. González; Luquin, Natasha; Farré, Daniel; Müller, Christian; Martínez‐Pinilla, Eva; Cortés, Antoni; Mallol, Josefa; Armentero, Marie Thérèse; Pinna, Annalisa; Canela, Enric I.; Lluı́s, Carme; McCormick, Peter J.; Lanciego, José L.; Casadó, Vicent; Franco, Rafael

doi:10.1016/j.neuropharm.2013.10.036

Cited by 81 publications

(67 citation statements)

References 68 publications

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“…By PLA experiments, Trifilieff et al [25] confirmed the existence of A 2A R-D 2 R complexes in striatal brain slices of wild-type mice ex vivo, showing a positive PLA signal that was significantly reduced in both D 2 R and A 2A R KO mice slices. Furthermore, using the same technique we detected the presence of A 2A R-D 2 R oligomers in monkey striatum [54] and in rat striatum via radioligand-binding experiments [55]. Significantly, these studies indicated that A 2A R-D 2 R heteromer formation might be disrupted in L-DOPAinduced dyskinetic animals [54,55].…”

Section: Confirmation Of a 2a R-d 2 R Heterotetramer Expression Ex Vivomentioning

confidence: 68%

“…Furthermore, using the same technique we detected the presence of A 2A R-D 2 R oligomers in monkey striatum [54] and in rat striatum via radioligand-binding experiments [55]. Significantly, these studies indicated that A 2A R-D 2 R heteromer formation might be disrupted in L-DOPAinduced dyskinetic animals [54,55]. Recently, Fernández-Dueñas et al [26] identified by PLA native A 2A R-D 2 R heteromers in the striatum of healthy rats which also decreased in the striatum of parkinsonian rats.…”

Section: Confirmation Of a 2a R-d 2 R Heterotetramer Expression Ex Vivomentioning

confidence: 75%

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Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Casadó-Anguera

Bonaventura

Moreno

et al. 2016

Biochemical Society Transactions

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Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D1receptor (D1R)-dopamine D3receptor (D3R) and adenosine A2Areceptor (A2AR)-dopamine D2receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A2AR-D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing theex vivoexpression of A2AR-D2R heteromers. The ability of A2AR agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A2AR-D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.

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Section: Confirmation Of a 2a R-d 2 R Heterotetramer Expression Ex Vivomentioning

confidence: 68%

Section: Confirmation Of a 2a R-d 2 R Heterotetramer Expression Ex Vivomentioning

confidence: 75%

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Casadó-Anguera

Bonaventura

Moreno

et al. 2016

Biochemical Society Transactions

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“…The samples were mounted and observed under a Leica SP2 confocal microscope and processed with ImageJ software. Cells containing one or more spots vs. total cells were determined considering 800-1,000 cells from between five and 12 different fields from three different animals per group using the Fiji package (pacific.mpi-cbg.de) as described previously (30).…”

Section: Fusion Proteins and Expressionmentioning

confidence: 99%

Allosteric interactions between agonists and antagonists within the adenosine A _2A receptor-dopamine D ₂ receptor heterotetramer

Bonaventura

Navarro

Casadó-Anguera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Adenosine A 2A receptor (A 2A R)-dopamine D 2 receptor (D 2 R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A 2A R-D 2 R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D 2 R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A 2A R agonists, but also A 2A R antagonists, decrease the affinity and intrinsic efficacy of D 2 R agonists and the affinity of D 2 R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A 2A R-D 2 R heteromers as heterotetramers, constituted by A 2A R and D 2 R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence com- Most evidence indicates that G protein-coupled receptors (GPCRs) form homodimers and heteromers. Homodimers seem to be a predominant species, and oligomeric entities can be viewed as multiples of dimers (1). It has been proposed that GPCR heteromers are constituted mainly by heteromers of homodimers (1, 2). Allosteric mechanisms determine a multiplicity of unique pharmacologic properties of GPCR homodimers and heteromers (1, 3). First, binding of a ligand to one of the receptors in the heteromer can modify the affinity of ligands for the other receptor (1, 3, 4). The most widely reproduced allosteric modulation of ligand-binding properties in a GPCR heteromer is the ability of adenosine A 2A receptor (A 2A R) agonists to decrease the affinity of dopamine D 2 receptor (D 2 R) agonists in the A 2A R-D 2 R heteromer (5). A 2A R-D 2 R heteromers have been revealed both in transfected cells (6, 7), striatal neurons in culture (6,8) and in situ, in mammalian striatum (9, 10), where they play an important role in the modulation of GABAergic striatopallidal neuronal function (9, 11).In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to the varying intrinsic efficacy of ligands for different signaling pathways (1-3). Intrinsic efficacy refers to the power of the agonist to induce a functional response, independent of its affinity for the receptor. Thus, allosteric modulation of an agonist can potentially involve changes in affinity and/or intrinsic efficacy (1, 3). This principle can be observed in the A 2A R-D 2 R heteromer, where a decrease in D 2 R agonist affinity cannot alone explain the ability of an A 2A R agonist to abolish the decreased excitability of GABAergic striatopallidal neurons induced by high concentration of a D 2 R agonist (9), which should overcome the decrease in affinity. Furthermore, a differential effect of allosteric modulations of different agonist-mediated signaling responses (i.e., functional selectivity) can occur within GPCR heteromers (1, 2, 8 It has been hypothesized that the allos...

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“…This socalled proximity ligation assay (PLA) confirmed the close proximity of various GPCR pairs in the central nervous system. In situ PLA between D 2 R and adenosine A 2A receptor (A 2A R) in the striatum of mice, rats, and monkeys (Trifilieff et al, 2011;Bonaventura et al, 2014;Fernández-Dueñas et al, 2015) confirmed D 2 R-A 2A R heteromer coimmunoprecipitation from the rat striatum (Cabello et al, 2009) as well as detection by coimmunoprecipitation, pull-down, FRET, BRET, and sequential BRET-FRET in heterologous cells (Canals et al, 2003;Kamiya et al, 2003;Cabello et al, 2009). Interestingly, in the striatum of an experimental Parkinsonism rat model, this PLA signal was significantly decreased as a consequence of reduced codistribution and proximity between D 2 R and A 2A R (Fernández-Dueñas et al, 2015).…”

Section: Detection Of Gpcr Dimers and Oligomers In Native Tissuesmentioning

confidence: 99%

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

Vischer

Castro

2015

Mol Pharmacol

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Heteromerization of G protein-coupled receptors (GPCRs) can significantly change the functional properties of involved receptors. Various biochemical and biophysical methodologies have been developed in the last two decades to identify and functionally evaluate GPCR heteromers in heterologous cells, with recent approaches focusing on GPCR complex stoichiometry and stability. Yet validation of these observations in native tissues is still lagging behind for the majority of GPCR heteromers. Remarkably, recent studies, particularly some involving advanced fluorescence microscopy techniques, are contributing to our current knowledge of aspects that were not well known until now, such as GPCR complex stoichiometry and stability. In parallel, a growing effort is being applied to move the field forward into native systems. This short review will highlight recent developments to study the stoichiometry and stability of GPCR complexes and methodologies to detect native GPCR dimers.

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l-DOPA-treatment in primates disrupts the expression of A2A adenosine–CB1 cannabinoid–D2 dopamine receptor heteromers in the caudate nucleus

Cited by 81 publications

References 68 publications

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Allosteric interactions between agonists and antagonists within the adenosine A _2A receptor-dopamine D ₂ receptor heterotetramer

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

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l-DOPA-treatment in primates disrupts the expression of A2A adenosine–CB1 cannabinoid–D2 dopamine receptor heteromers in the caudate nucleus

Cited by 81 publications

References 68 publications

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Allosteric interactions between agonists and antagonists within the adenosine A 2A receptor-dopamine D 2 receptor heterotetramer

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

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Allosteric interactions between agonists and antagonists within the adenosine A _2A receptor-dopamine D ₂ receptor heterotetramer