Differential activation of G protein-mediated signaling by synthetic cannabinoid receptor agonists.

ABSTRACT: Synthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear-including the potential differential activation of G protein subtypes by cannabinoid receptor type 1 (CB1), a major target of SCRA. We measured CB1-mediated activation of G?s and G?i/o proteins by SCRAs by examining stimulation (pertussis toxin, PTX treated) as well as inhibition (non-PTX treated) of forskolin (FSK)-induced cyclic adenosine monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably expressing CB1. Real-time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 µmol L-1 ), increased cAMP levels 12%-45% above that produced by FSK alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX-treated HEK-CB1 cells. All SCRAs had greater potency to inhibit FSK-induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (G?s ) was PB-22 > 5F-MDMB-PICA > JWH-018 ? AB-FUBINACA > XLR-11. By contrast, the potency of SCRAs for inhibition of cAMP (G?i/o ) was 5F-MDMB-PICA > AB-FUBINACA > PB-22 > JWH-018 > XLR-11. The different rank order of potency and EMax  of the SCRAs to stimulate G?s -like signaling compared to G?i/o signaling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.

SUBMITTER: Sachdev S 

PROVIDER: S-EPMC7043210 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature