title: Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex.
abstract: Cannabinoid receptors are able to couple to different families of G proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, Δ9-THC, WIN55212-2, and ACEA in mouse brain cortex. Stimulation of the [35S]GTPγS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13), in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 μM) was determined by scintillation proximity assay (SPA) technique in mouse cortex of wild type, CB1knock-out, CB2knock-out and CB1/CB2double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/osubunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1and/or CB2receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHULeioa, Spain; Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Diez-Alarcia
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU Leioa, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Ibarra-Lecue
authors.affiliation: Department of Animal Reproduction, Instituto Nacional de Tecnología Agraria y AlimentariaMadrid, Spain; G.I. Biogénesis, Universidad de AntioquiaAntioquia, Colombia.
authors.forename: Ángela P
authors.initials: ÁP
authors.lastname: Lopez-Cardona
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHULeioa, Spain; Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Meana
authors.affiliation: Department of Animal Reproduction, Instituto Nacional de Tecnología Agraria y Alimentaria Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutierrez-Adán
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHULeioa, Spain; Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.affiliation: Department of Physiology, University of the Basque Country Leioa, Spain.
authors.forename: Ekaitz
authors.initials: E
authors.lastname: Agirregoitia
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHULeioa, Spain; Centro de Investigación Biomédica en Red de Salud MentalMadrid, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Urigüen
keywords: CB1 receptor; CB2 receptor; G proteins; brain; functional selectivity; scintillation proximity assay (SPA)