FIGURE 9.

Schematic representation of OPRM1-Gα_i2-Src kinase signaling pathway in lipid rafts. A, lipid raft microdomains contain OPRM1, Gα_i2, Src kinases, AC, and flotillin-1 (Flo-1), a lipid raft marker that is also known to anchor the signaling molecules, such as Src kinases (69) and G-proteins (L. Zhang and P.-Y. Law, unpublished observation) in lipid raft. There is another pool of OPRM1 located outside the lipid raft. B, under the acute agonist treatment, OPRM1 interacts with Gα_i2 and causes the inhibition of adenylyl cyclase activity and the decrease of intracellular cAMP level (31). After chronic agonist treatment, Src kinase is recruited by OPRM1-Gα_i2 signal complex, and it is activated by autophosphorylation at Tyr⁴¹⁶. The activated Src will phosphorylate the OPRM1 at Tyr³³⁶. Although the exact mechanism has yet to be elucidated, the phosphorylated and activated OPRM1-Gα_i2-Src signaling complex, either directly or indirectly by activating other protein kinases, phosphorylates AC isoforms, such as AC 5/6 (14, 15), and other signaling molecules (16), eventually leads to the observed AC activation.