scholarly journals The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons

2021 ◽  
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Luca Ferraro ◽  
Sarah Beggiato ◽  
Manuel Narváez ◽  
Ramon Fores-Pons ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Dopamine D2 Receptor ◽  
Tyrosine Phosphatase ◽  
D2 Receptor ◽  
Growth Factor Receptor ◽  
General Mechanism ◽  
Nucleus Accumbens Shell ◽  
Metabotropic Glutamate ◽  
Gaba Neurons ◽  
Adenosine A2a

AbstractThe role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate receptor 5 (mGluR5) in the striatal-pallidal GABA neurons appears necessary for phosphorylation of the GluA1 unit of the AMPA receptor to take place. Robert Yasuda (J Neurochem 152: 270–272, 2020) focused on finding a general mechanism by which STEP activation is enhanced by increased A2AR transmission in striatal-pallidal GABA neurons expressing A2AR and dopamine D2 receptor. In his Editorial, he summarized in a clear way the significant effects of A2AR activation on STEP in the dorsal striatal-pallidal GABA neurons which involves a rise of intracellular levels of calcium causing STEP activation through its dephosphorylation. However, the presence of the A2AR in an A2AR-fibroblast growth factor receptor 1 (FGFR1) heteroreceptor complex can be required in the dorsal striatal-pallidal GABA neurons for the STEP activation. Furthermore, Won et al. (Proc Natl Acad Sci USA 116: 8028–8037, 2019) found in mass spectrometry experiments that the STEP splice variant STEP61 can bind to mGluR5 and inactivate it. In addition, A2AR overexpression can lead to increased formation of A2AR-mGluR5 heterocomplexes in ventral striatal-pallidal GABA neurons. It involves enhanced facilitatory allosteric interactions leading to increased Gq-mediated mGluR5 signaling activating STEP. The involvement of both A2AR and STEP in the actions of cocaine on synaptic downregulation was also demonstrated. The enhancement of mGluR5 protomer activity by the A2AR protomer in A2AR-mGluR5 heterocomplexes in the nucleus accumbens shell appears to have a novel significant role in STEP mechanisms by both enhancing the activation of STEP and being a target for STEP61.

scholarly journals Allosteric mechanisms within the adenosine A2A–dopamine D2 receptor heterotetramer

2016 ◽  
Vol 104 ◽  
pp. 154-160 ◽  
Author(s):  
Sergi Ferré ◽  
Jordi Bonaventura ◽  
Dardo Tomasi ◽  
Gemma Navarro ◽  
Estefanía Moreno ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Allosteric Mechanisms ◽  
Adenosine A2a

scholarly journals Revealing Adenosine A2A-Dopamine D2 Receptor Heteromers in Parkinson’s Disease Post-Mortem Brain through a New AlphaScreen-Based Assay

2019 ◽  
Vol 20 (14) ◽  
pp. 3600 ◽  
Author(s):  
Víctor Fernández-Dueñas ◽  
Maricel Gómez-Soler ◽  
Marta Valle-León ◽  
Masahiko Watanabe ◽  
Isidre Ferrer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dynamic Range ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Post Mortem ◽  
Dopamine D2 ◽  
Post Mortem Brain ◽  
Receptor Heteromers ◽  
Adenosine A2a

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson’s disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity.

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

2016 ◽  
Vol 44 (2) ◽  
pp. 595-600 ◽  
Author(s):  
Verònica Casadó-Anguera ◽  
Jordi Bonaventura ◽  
Estefanía Moreno ◽  
Gemma Navarro ◽  
Antoni Cortés ◽  
...  
Keyword(s):  
Structural Model ◽  
Dopamine D2 Receptor ◽  
Ex Vivo ◽  
D2 Receptor ◽  
Drug Dosage ◽  
D1 Receptor ◽  
Structural Basis ◽  
Dopamine D2 ◽  
Allosteric Mechanisms ◽  
Adenosine A2a

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 other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing the ex vivo expression 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.

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex

2018 ◽  
Vol 47 (9) ◽  
pp. 1127-1134 ◽  
Author(s):  
Joana I. Real ◽  
Ana Patrícia Simões ◽  
Rodrigo A. Cunha ◽  
Samira G. Ferreira ◽  
Daniel Rial
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Transmission ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Dopamine D2 ◽  
Adenosine A2a
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