Allosteric interactions between agonists and antagonists within the adenosine A 2A receptor-dopamine D 2 receptor heterotetramer (original) (raw)
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Homodimerization of adenosine A1 receptors in brain cortex explains the biphasic effects of caffeine
Neuropharmacology, 2013
Using bioluminescence resonance energy transfer and proximity ligation assays, we obtained the first direct evidence that adenosine A 1 receptors (A 1 Rs) form homomers not only in cell cultures but also in brain cortex. By radioligand binding experiments in the absence or in the presence of the A 1 Rs allosteric modulator, adenosine deaminase, and by using the two-state dimer receptor model to fit binding data, we demonstrated that the protomer-protomer interactions in the A 1 R homomers account for some of the pharmacological characteristics of agonist and antagonist binding to A 1 Rs. These pharmacological properties include the appearance of cooperativity in agonist binding, the change from a biphasic saturation curve to a monophasic curve in self-competition experiments and the molecular cross-talk detected when two different specific molecules bind to the receptor. In this last case, we discovered that caffeine binding to one protomer increases the agonist affinity for the other protomer in the A 1 R homomer, a pharmacological characteristic that correlates with the low caffeine concentrationsinduced activation of agonist-promoted A 1 R signaling. This pharmacological property can explain the biphasic effects reported at low and high concentration of caffeine on locomotor activity.
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.
The Journal of …, 2006
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 A 1 R-A 2A R heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A 1 R-A 2A R heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
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...
International Journal of Molecular Sciences, 2021
Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A2AR/D2R heteromeric ...
Journal of Biological Chemistry, 2003
There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs). Although a close physical interaction between both receptors has recently been shown using co-immunoprecipitation and co-localization assays, the existence of a A2AR-D2R protein-protein interaction still had to be demonstrated in intact living cells. In the present work, fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) techniques were used to confirm the occurrence of A2AR-D2R interactions in co-transfected cells. The degree of A2AR-D2R heteromerization, measured by BRET, did not vary after receptor activation with selective agonists, alone or in combination. BRET competition experiments were performed using a chimeric D2R-D1R in which helices 5 and 6, the third intracellular loop (I3), and the third extracellular loop (E3) of the D2R were replaced by those of the dopamine D1 receptor (D1R). Although the wild type D2R 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 D2R holds the site(s) for interaction with A2AR. Modeling of A2AR and D2R using a modified rhodopsin template followed by molecular dynamics and docking simulations gave essentially two different possible modes of interaction between D2R and A2AR. In the most probable one, helix 5 and/or helix 6 and the N-terminal portion of I3 from D2R approached helix 4 and the C-terminal portion of the C-tail from the A2AR, respectively.
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 A2A and Dopamine D2 Heteromeric Receptor Complexes and Their Function
Journal of Molecular Neuroscience, 2005
The existence of A 2A -D 2 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 A 2A and D 2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A 2A -D 2 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 A 2A and D 2 agonists. The A 2A -D 2 heteromers could either be A 2A -D 2 heterodimers and/or higher-order A 2A -D 2 hetero-oligomers. In striatal neurons there are probably A 2A -D 2 heteromeric complexes, together with A 2A -D 2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A 2A and D 2 signaling in the striatopallidal GABA neurons. Through the use of D 2 /D 1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D 2 receptor are part of the A 2A -D 2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D 2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A 2A receptor. Computerized modeling of A 2A -D 2 heteromers are in line with these findings. It seems likely that A 2A receptor-induced reduction of D 2 receptor recognition, G protein coupling, and signaling, as well as the existence of A 2A -D 2 co-trafficking, are the consequence of the existence of an A 2A -D 2 receptor heteromer. The relevance of A 2A -D 2 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 A 2A -D 3 heteromeric receptor complexes in cotransfected cell lines has been summarized.