title: Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R.
abstract: 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.
authors.affiliation: Unitat de Farmacologia, Facultat de Medicina, Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Maricel
authors.initials: M
authors.lastname: Gómez-Soler
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Santhosh T
authors.initials: ST
authors.lastname: Kumar
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D001120:Arginine / Q000235:genetics; D018491:Dopamine Agonists / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D019257:Quinpirole / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D018491:Dopamine Agonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D001120:Arginine