title: Uncovering caffeine's adenosine A2A receptor inverse agonism in experimental parkinsonism.
abstract: Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson's disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A2A receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the receptor's activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona , L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Maricel
authors.initials: M
authors.lastname: Gómez-Soler
authors.forename: Marc
authors.initials: M
authors.lastname: López-Cano
authors.forename: Jaume J
authors.initials: JJ
authors.lastname: Taura
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020734:Parkinsonian Disorders; D043705:Receptor, Adenosine A2A / Q000187:drug effects*
chemical_list: D043705:Receptor, Adenosine A2A; D002110:Caffeine