Role of the highly conserved Asp-Arg-Tyr motif in signal transduction of the CB₂ cannabinoid receptor

The DRY motif, at the junction of transmembrane helix 3 and intracellular loop 2 of G protein-coupled receptors, is highly conserved. Mutations were introduced into the CB₂ cannabinoid receptor to study the role of this motif in CB₂ signaling. D mutations (DRY130-132AAA and D130A) markedly reduced binding of cannabinoid agonists, while no significant reduction was observed with R131A or Y132A. Mutating R (R131A) only partially reduced, and mutating Y (Y132A) more efficiently reduced the cannabinoid- induced inhibition of adenylyl cyclase. Thus, in CB₂, D130 is involved in agonist binding, whereas Y seems to have a role in receptor downstream signaling. (C) 2000 Federation of European Biochemical Societies.