In this study, we investigated the role of CB1palmitoylation in modulating the functional interaction with G proteins both in the absence and presence of agonist binding. Our data show that the nonpalmitoylated CB1receptor significantly reduced its association with Gαi2. The agonist stimulation induced a partial dissociation of Gαi2proteins from the wild-type receptor, while on the C415A mutant the agonist binding was not able to induce a significant dissociation of Gαi2from the receptor. The lack of palmitoyl chain seems to hamper the ability of the receptor to functionally interact with the Gαi2and indicate that the palmitoyl chain is responsible for the functional transmission of the agonist-induced conformational change in the receptor of the G protein. These data were further corroborated by molecular dynamics simulations. Overall these results suggest that palmitoylation of the CB1receptor finely tunes its interaction with G proteins and serves as a targeting signal for its functional regulation. Of note, the possibility to reversibly modulate the palmitoylation of CB1receptor may offer a coordinated process of regulation and could open new therapeutic approaches.
- Journal Article