Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

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 (Gα_i1, Gα_i2, Gα_i3, Gα_o, Gα_z, Gα_s, Gα_q/11, and Gα_12/13), 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, CB₁ knock-out, CB₂ knock-out and CB₁/CB₂ double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gα_i/o subunits but also other G subunits like Gα_z, Gα_q/11, and Gα_12/13. 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 CB₁ and/or CB₂ receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.