title: A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase.
abstract: A2ARs (adenosine A2A receptors) are highly enriched in the striatum, which is the main motor control CNS (central nervous system) area. BRET (bioluminescence resonance energy transfer) assays showed that A2AR homomers may act as cell-surface ADA (adenosine deaminase; EC 3.5.4.4)-binding proteins. ADA binding affected the quaternary structure of A2ARs present on the cell surface. ADA binding to adenosine A2ARs increased both agonist and antagonist affinity on ligand binding to striatal membranes where these proteins are co-expressed. ADA also increased receptor-mediated ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Collectively, the results of the present study show that ADA, apart from regulating the concentration of extracellular adenosine, may behave as an allosteric modulator that markedly enhances ligand affinity and receptor function. This powerful regulation may have implications for the physiology and pharmacology of neuronal A2ARs.
authors.affiliation: Centro de Investigacón Biomédica en Red sobre Enfermedades Neurodegenerativas, and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gracia
authors.forename: Kamil
authors.initials: K
authors.lastname: Pérez-Capote
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.forename: Jana
authors.initials: J
authors.lastname: Barkešová
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D001921:Brain; D016466:CHO Cells; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018080:Receptors, GABA-B; D000243:Adenosine Deaminase