Abstract

Anandamide activates CB(1) cannabinoid receptors but also has effects, particularly in the vasculature, that cannot be explained by actions at either this or the other cloned cannabinoid receptor, the CB(2) receptor. These effects are probably mediated by a novel G protein-coupled receptor, but genome searching has not revealed a strong candidate. Several approaches have suggested that an orphan receptor, GPR55, is a target for anandamide, but the pharmacology of this receptor is such that it cannot be categorically identified as a cannabinoid receptor. GPR55 appears primarily to be a receptor for lysophosphatidylinositol which may exhibit biased agonism, leading to it also responding to anandamide. GPR55 activates G(alpha12) and G(alpha13) and thence RhoA, leading to an oscillatory intracellular Ca(2+) signal. Further complexity arises from possible interactions between the anandamide-sensitive CB(1) receptor and GPR55. Overall, it appears that GPR55 has several signaling modalities and that, while anandamide can activate systems containing this receptor, GPR55 cannot yet be primarily designated a receptor for this endocannabinoid.