title: The role of parkinson's disease-associated receptor GPR37 in the hippocampus: functional interplay with the adenosinergic system.
abstract: GPR37 is an orphan G protein-coupled receptor mostly enriched in brain areas such as the cerebellum, striatum, and hippocampus. Identified as a substrate of parkin, GPR37 has been suggested to play a role in Parkinson's disease. Distributed throughout the brain, the function of GPR37, however, remains unknown. We now provide the first mapping of GPR37 within the hippocampus, where GPR37 is widely expressed and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts, and axon terminals. GPR37 per se does not appear to play a role in learning and memory, since knocking out GPR37 (GPR37-KO) did not alter the performance in different hippocampal-related memory tasks. This is in agreement with slice electrophysiology experiments showing no differences both in short-term plasticity paired-pulse facilitation and long-term potentiation between WT and GPR37-KO mice. However, we report a potential functional interaction between GPR37 and adenosine A2A receptors (A2 A R) in the hippocampus, with A2 A R modulating the GPR37-associated phenotype. Thus, the absence of GPR37 appeared to sensitize mice to hippocampal A2 A R-mediated signaling, as observed by the effect of the A2 A R antagonist SCH58261 increasing synaptic depotentiation, reducing novel object recognition memory and reverting the anxiolytic effect of GPR37 deletion. Collectively, these findings afford insight into the localization and role of the orphan GPR37 within the hippocampus with potential involvement in A2 A R function (i.e., A2 A R sensitization). GPR37 is an orphan G protein-coupled receptor widely expressed in the hippocampus and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals. This orphan receptor per se does not appear to directly control the learning and memory processes; however knocking-out GPR37 triggers anxiolytic-like effects and sensitizes mice to hippocampal A2A R-mediated signalling.
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: João P
authors.initials: JP
authors.lastname: Lopes
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Morató
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Souza
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Cindy
authors.initials: C
authors.lastname: Pinhal
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Nuno J
authors.initials: NJ
authors.lastname: Machado
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Canas
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Henrique B
authors.initials: HB
authors.lastname: Silva
authors.affiliation: Department of Biochemistry and Department of Molecular Genetics, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gandía
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.affiliation: Departamento de Ciencias Médicas, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Facultad de Medicina, Universidad Castilla-La Mancha, Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.affiliation: CNC-Center for Neurosciences and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.|Department of Physiology, Faculty of Sciences, University of Ghent, Gent, Belgium.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000032:analysis / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000502:physiology*
chemical_list: C509804:Gpr37 protein, mouse; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled
keywords: GPR37; adenosine A2A receptor; hippocampus; synaptic plasticity