Regulator of G protein signaling 6 (RGS6) controls the effect of cannabinoids on intestinal tract motility and visceral pain sensation in mice

Background Gastrointestinal (GI) tract diseases cause symptoms that significantly affect the quality of life. A promising direction in the search for novel therapeutic options in this field is the investigation of G protein-coupled receptors (GPCRs), whose activity is modulated by their regulator proteins (RGS). In this study, we examined RGS6 involvement in GI inflammation and functional disorders and its effect on cannabinoid (CB), opioid, and serotonin receptor (5HTR)-targeting compounds, Methods Using quantitative PCR, western blot, and ELISA assays, we characterized RGS6 expression in the mouse GI tract and measured GPCR-related secondary messenger expression upon stimulation with GPCR agonists in vitro in Caco-2 cells, both wild type (WT) and RGS6 knock-out (KO). Then, in vivo in a dextran sulfate sodium (DSS) mouse model of colitis using WT, global and tissue-specific RGS6 KO mice, inflammation, antinociceptive effects, and GI motility were examined. Results In Caco-2 cells, we found that RGS6 KO increased extracellular signal-regulated kinase phosphorylation, which was blocked by CB agonist WIN 55,212-2. Moreover, incubation with WIN 55,212-2 significantly reduced cyclic adenosine monophosphate (cAMP) levels in RGS6 KO but not WT cells. In DSS-induced, acute and chronic-relapsing mouse models of colitis, RGS6 KO resulted in resistance to stress-induced GI hypermotility. WIN 55,212-2 (1 mg/kg ip) substantially prolonged GI transit time and displayed antinociceptive properties that were stronger in the absence of RGS6. Epithelial -specific RGS6 KO did not affect the action of WIN 55,212-2. Conclusions RGS6 exerts crucial effects on GI physiology by acting on CB signaling in the enteric and/or central nervous system.