Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices

Borroto-Escuela, Dasiel O.; Romero-Fernández, Wilber; Tarakanov, Alexander O.; Gómez-Soler, Maricel; Corrales, Fernando J.; Marcellino, Daniel; Narváez, Manuel; Frankowska, Małgorzata; Flajolet, Marc; Heintz, Nathaniel; Agnati, Luigi F.; Ciruela, Francisco

doi:10.1016/j.bbrc.2010.10.122

Cited by 89 publications

(85 citation statements)

References 14 publications

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“…Surprisingly, and at odds with previously published studies (Borroto-Escuela et al, 2010), the application of peptides (4-40 mM for 60 minutes) significantly inhibited the enzymatic activity of Rluc, with strong reduction of bioluminescence values. Reductions about 50% were obtained at peptide concentrations of 40 mM, which, in our hands, invalidates BRET as a method to evaluate modifications of receptor heteromer structure induced by synthetic hydrophobic TM-like peptides.…”

Section: Resultscontrasting

confidence: 98%

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

Guitart¹,

Navarro²,

Moreno³

et al. 2014

Mol Pharmacol

115

111

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The dopamine D 1 receptor-D 3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa-induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques, and cell-signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R-D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to G s and G i proteins, respectively. Coactivation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of b-arrestin-1, and to a positive cross talk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted b-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive cross talk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of yellow fluorescence protein fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists.

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Section: Resultscontrasting

confidence: 98%

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

Guitart¹,

Navarro²,

Moreno³

et al. 2014

Mol Pharmacol

115

111

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“…Previous BRET experiments with disrupting peptides had suggested the involvement of TM5 from D 2 R in A 2A R-D 2 R heteromerization (18). We investigated whether synthetic peptides with the sequence of TM5 and TM7 of A 2A R or D 2 R fused to HIV TAT were able to destabilize receptor heteromerization.…”

Section: Resultsmentioning

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.

137

220

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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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“…The receptor interface between two GPCRs can involve a-helix -helix interactions between transmembrane domains (e.g. [98]), and intracellular electrostatic interactions between intracellular loop 3 (IC3) of one protomer and the C-terminal tail of the other play a major role [99,100]. Often, positively charged arginins in the IC3 segment of one protomer interact with negatively charged residues in the C-terminal tail of the other, especially phosphorylated serine and glutamate residues.…”

Section: (B) On the Renewal And Clearance Of Volume Transmission Signmentioning

confidence: 99%

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

Borroto-Escuela

Agnati

Bechter

et al. 2015

Phil. Trans. R. Soc. B

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135

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One contribution of 16 to a discussion meeting issue 'Release of chemical transmitters from cell bodies and dendrites of nerve cells'. Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane.

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Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices

Cited by 89 publications

References 14 publications

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

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

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

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Characterization of the A2AR–D2R interface: Focus on the role of the C-terminal tail and the transmembrane helices

Cited by 89 publications

References 14 publications

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D1-D3 Receptor Heterotetramer

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D1-D3 Receptor Heterotetramer

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

The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks

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Product

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Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

Functional Selectivity of Allosteric Interactions within G Protein–Coupled Receptor Oligomers: The Dopamine D₁-D₃ Receptor Heterotetramer

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