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Molecular determinants of A 2A R–D 2 R allosterism: role of the intracellular loop 3 of the D 2 R
Author(s) -
FernándezDueñas Víctor,
GómezSoler Maricel,
Jacobson Kenneth A.,
Kumar Santhosh T.,
Fuxe Kjell,
BorrotoEscuela Dasiel O.,
Ciruela Francisco
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07956.x
Subject(s) - allosteric regulation , receptor , chemistry , förster resonance energy transfer , intracellular , agonist , allosteric modulator , biophysics , oligomer , quinpirole , stereochemistry , biochemistry , biology , fluorescence , physics , organic chemistry , quantum mechanics
In the CNS , an antagonistic interaction has been shown between adenosine A 2A and dopamine D 2 receptors (A 2 A R s 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 2 A 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 2 A 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 2 A 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 2 A R /D 2 R oligomer in living cells.