title: A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.
abstract: Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders.
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Genova, Italy.|Centre of Excellence for Biomedical Research CEBR, University of Genova, Viale Benedetto, Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cervetto
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Genova, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Venturini
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, and Italian Institute of Biostructures and Biosystems, University of Genova, Genova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.affiliation: Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Guidolin
authors.affiliation: Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Genedani
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Esquela
authors.affiliation: Department of Biomedical and NeuroMotor Sciences DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy.|IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cortelli
authors.affiliation: Structural Biology Unit, National Institutes of Health, National Institute of Drug Abuse-Intramural Research Program, Baltimore, MD, USA.
authors.forename: Amina
authors.initials: A
authors.lastname: Woods
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Genova, Italy.|Centre of Excellence for Biomedical Research CEBR, University of Genova, Viale Benedetto, Genova, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Maura
authors.affiliation: Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Genova, Italy.|Centre of Excellence for Biomedical Research CEBR, University of Genova, Viale Benedetto, Genova, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marcoli
authors.affiliation: Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D017072:Neostriatum / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D018698:Glutamic Acid; D000241:Adenosine
keywords: Receptor-receptor interactions; astrocyte processes; glutamate; heterodimers