Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer
| Autor: | Antoni Cortés, Carme Lluís, Sergi Ferré, Jordi Bonaventura, Gemma Navarro, Enric I. Canela, Verònica Casadó-Anguera, Marc Brugarolas, Vicent Casadó, Estefanía Moreno, Josefa Mallol, Karima Azdad, Nora D. Volkow, Serge N. Schiffmann, William Rea |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Bioluminescence Resonance Energy Transfer Techniques
Male Adenosine Time Factors Intrinsic activity Adenosine A2 Receptor Agonists Receptor Adenosine A2A Dopamine Allosteric regulation Adenosina Heteromer Adenosine A2A receptor Dopamina CHO Cells Pharmacology Binding Competitive Rats Sprague-Dawley Cricetulus Dopamine receptor D2 Caffeine Cricetinae medicine Animals Humans Receptor Multidisciplinary Microscopy Confocal Sheep Dose-Response Relationship Drug Chemistry Receptors Dopamine D2 Heterotetramer Corpus Striatum Adenosine A2 Receptor Antagonists Dopamine D2 Receptor Antagonists Kinetics HEK293 Cells PNAS Plus Cafeïna Dopamine Agonists Biophysics Protein Multimerization medicine.drug Protein Binding |
| Popis: | Significance G protein-coupled receptors (GPCRs) constitute the largest plasma membrane protein family involved in cell signaling. GPCR homodimers are predominant species, and GPCR heteromers likely are constituted by heteromers of homodimers. The adenosine A 2A receptor (A 2A R)-dopamine D 2 receptor (D 2 R) heteromer is a target for the nonselective adenosine receptor antagonist caffeine. This study uncovers allosteric modulations of A 2A R antagonists that mimic those of A 2A R agonists, challenging the traditional view of antagonists as inactive ligands. These allosteric modulations disappear when agonist and antagonist are coadministered, however. A model is proposed that considers A 2A R-D 2 R heteromers as heterotetramers, constituted by A 2A R and D 2 R homodimers. The model predicted that high concentrations of A 2A R antagonists would behave as A 2A R agonists and decrease D 2 R function in the brain. |
| Databáze: | OpenAIRE |
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