Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R (original) (raw)

2012, Journal of neurochemistry

In the CNS, an antagonistic interaction has been shown between adenosine A 2A and dopamine D 2 receptors (A 2A Rs and D 2 Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptor-receptor interaction have recently been explored, as the fine tuning of this target (namely the A 2A R/D 2 R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer-based approach to examine the allosteric modulation of the D 2 R within the A 2A R/D 2 R oligomer and the dependence of this receptor-receptor interaction on two regions rich in positive charges on intracellular loop 3 of the D 2 R. Interestingly, we observed a negative allosteric effect of the D 2 R agonist quinpirole on A 2A R ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217-222 and 267-269) on intracellular loop 3 of the D 2 R, thus demonstrating a major role of these positively charged residues in mediating the observed receptor-receptor interaction. Overall, these results provide structural insights to better understand the functioning of the A 2A R/D 2 R oligomer in living cells. resonance energy transfer; HEK, Human embryonic kidney; IL3, third intracellular loop 3; RIPA, radio immunoprecipitation assay .

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