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The recently cloned GB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB, receptor subtype. The binding of rH] CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 rlM, respectively) and saturable. In competitive binding experiments,(-)-9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 21 0 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanol-amides dihomo-y-Iinolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the GB1 and GB2 receptors was mim-icked in functional inhibition of cAMP accumulation experi-ments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumlation that was pertussis toxin sensitive. SRi 41 71 6A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and func-tional inhibition of cAMP accumlation experiments. When ex-pressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the GB2 receptor did not …