Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1–CB2 Heteroreceptor Complexes

Abstract

Cannabigerol (CBG) is one of the major phytocannabinoids present in <i>Cannabis sativa</i> L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB₁ (CB₁R) and CB₂ (CB₂R) receptors and the effects of the compound on agonist activation of those receptors and of CB₁-CB₂ heteroreceptor complexes. Using [³H]-CP-55940, CBG competed with low micromolar <i>K</i>_i values the binding to CB₁R and CB₂R. Homogeneous binding in living cells, which is only technically possible for the CB₂R, provided a 152 nM <i>K</i>_i value. Also interesting, CBG competed the binding of [³H]-WIN-55,212-2 to CB₂R but not to CB₁R (<i>K</i>_i: 2.7 versus >30 μM). The phytocannabinoid modulated signaling mediated by receptors and receptor heteromers even at low concentrations of 0.1-1 μM. cAMP, pERK, β-arrestin recruitment and label-free assays in HEK-293T cells expressing the receptors and treated with endocannabinoids or selective agonists proved that CBG is a partial agonist of CB₂R. The action on cells expressing heteromers was similar to that obtained in cells expressing the CB₂R. The effect of CBG on CB₁R was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.