Adenosine A2A and Dopamine D2 Heteromeric Receptor Complexes and Their Function (original) (raw)
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Adenosine A 2A and dopamine D 2 heteromeric receptor complexes and their function
Journal of Molecular Neuroscience, 2005
The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A-D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the 13 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of 13 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson’s disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.
Allosteric mechanisms within the adenosine A2A–dopamine D2 receptor heterotetramer
Neuropharmacology, 2016
The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The wellknown agonist/agonist allosteric interaction in the adenosine A 2A receptor (A 2A R)-dopamine D 2 receptor (D 2 R) heteromer, by which A 2A R agonists decrease the affinity of D 2 R agonists, gave the first rationale for the use of A 2A R antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A 2A R-D 2 R heteromer: first, ligand-independent allosteric modulations by the D 2 R that result in changes of the binding properties of A 2A R ligands; second, differential modulation of the intrinsic efficacy of D 2 R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A 2A R antagonists, including caffeine, to also exert the same allosteric modulations of D 2 R ligands than A 2A R agonists, while A 2A R agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A 2A R antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D 2 R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies.
Adenosine A 2A-dopamine D 2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders
Parkinsonism & Related Disorders, 2004
BRET competition experiments were performed using a chimeric D 2 R-D 1 R in which helices 5 and 6, the third intracellular loop (I3), and the third extracellular loop (E3) of the D 2 R were replaced by those of the dopamine D 1 receptor (D 1 R). Although the wild type D 2 R was able to decrease the BRET signal, the chimera failed to achieve any effect. This suggests that the helix 5-I3-helix 6-E3 portion of D 2 R holds the site(s) for interaction with A 2A R.
Evidence for the heterotetrameric structure of the adenosine A2A-dopamine D2 receptor complex
Biochemical Society Transactions, 2016
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 D1 receptor (D1R)–dopamine D3 receptor (D3R) and adenosine A2A receptor (A2AR)–dopamine D2 receptor (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 oth...
Recently evidence has been presented that adenosine A 2A and dopamine D 2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk Ϫ cells. These A 2A /D 2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D 2 or A 2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A 2A /D 2 receptor heteromer represents the molecular basis for the antagonistic A 2A /D 2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A 2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A 2A /mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D 2 , A 2A , and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D 2 /A 2A /mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.
Neurochemistry International, 2013
The molecular interaction between adenosine A 2A and dopamine D 2 receptors (A 2A Rs and D 2 Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A 2A R challenge on D 2 R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D 2 R-mediated allosteric modulation of A 2A R binding when an A 2A R/D 2 R oligomer is established. Thus, we synthesized fluorescent A 2A R agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A 2A R binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D 2 R-mediated negative allosteric modulation on A 2A R agonist binding that was oligomerformation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A 2A R agonist binding. Overall, the here-developed methods were found valid to prospect the ability of drugs acting on D 2 Rs to modulate A 2A R binding, thus featuring as possible helpful tools for the preliminary selection of D 2 R-like candidate drugs in the management of Parkinson's disease.
Journal of Biological Chemistry, 2002
Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A 2A receptors (A 2A R) and dopamine D 2 receptors (D 2 R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D 2 R and in cultured striatal cells. A 2A R/D 2 R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D 2 R-transfected SH-SY5Y cells and from mouse fibroblast Ltk ؊ cells stably transfected with human D 2 R (long form) and transiently cotransfected with the A 2A R double-tagged with hemagglutinin. Long term exposure to A 2A R and D 2 R agonists in D 2 R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A 2A R and D 2 R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D 2 R are involved.
Adenosine A 2A receptors, dopamine D 2 receptors and their interactions in Parkinson's disease
Movement Disorders, 2007
Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A 2A /D 2 heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A 2A /D 2 receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A 2A antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D 2 signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A 2A activated adenylyl cyclase by persistent D 2 activation and a compensatory up-regulation of A 2A receptors in response to intermittent Levodopa treatment. An increased dominance of A 2A homomers over D 2 homomers and A 2A /D 2 heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A 2A antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigrostriatal DA system.
Journal of Neural Transmission, 2007
The molecular basis for the known intramembrane receptorreceptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D 2 dopamine and A 2A adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D 1 dopamine and A 1 adenosine receptors is reviewed. Heteromers formed by dopamine D 1 and D 2 receptors and by adenosine A 1 and A 2A receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor-receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor-receptor and receptor-protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.