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, 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 Gαi/o subunits 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 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.
Highlights
During the last decade a wide number of studies have focused on the potential involvement of the endocannabinoid system in a variety of psychiatric and neurological disorders
Different or opposite behavioral effects have been observed after the administration of 9-THC or synthetic cannabinoid ligands (Fattore et al, 2003; Panagis et al, 2014; Rubino and Parolaro, 2016)
The inhibitory subunits Gαo and Gαz, which were significantly stimulated in the wild type (WT) mice, remained stimulated in the CB1−/− (111 ± 2% for Gαo and 123 ± 7% for Gαz) but not stimulation was found in the CB2−/− nor in the CB1−/−/CB2−/− mice. These results suggest that the inhibitory signaling of WIN55212-2 in the mice brain through Gαi1 and Gαi3 activation seems to be mediated by the CB1 receptor, while the stimulation of Gαo and Gαz would be mediated by the CB2 receptor activation
Summary
During the last decade a wide number of studies have focused on the potential involvement of the endocannabinoid system in a variety of psychiatric and neurological disorders. 2-arachidonoylglycerol (2-AG) act primarily through cannabinoid CB1 and CB2 receptors. These cannabinoid receptors are GPCRs mostly coupled to Gi/o proteins (Howlett et al, 2002). The CB1 receptor is mainly distributed in the CNS, in cortex, basal ganglia, hippocampus, and cerebellum (Mackie, 2005; De Jesus et al, 2006) and generally acts presinaptically inhibiting the release of neurotransmitters. CB2 receptors are expressed at much lower levels in the CNS compared with CB1 receptors (reviewed in Atwood and Mackie, 2010). As Gi/o coupled GPCRs, CB1 and CB2 receptors inhibit adenylyl cyclase, but both receptors are able to activate MAPK, inhibit voltage gated Ca2+ channels and activate inwardly rectifying K+ channels (Childers et al, 1993)
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