Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer
Abstract
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 A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer is a target for the nonselective adenosine receptor antagonist caffeine. This study uncovers allosteric modulations of A2AR antagonists that mimic those of A2AR 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 A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers. The model predicted that high concentrations of A2AR antagonists would behave as A2AR agonists and decrease D2R function in the brain.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- July 2015
- DOI:
- 10.1073/pnas.1507704112
- Bibcode:
- 2015PNAS..112E3609B