Fig. 1.

The GPCR cycle. The GPCR cycle starts on the top left of the figure. In its basal state, a GPCR is free of ligand (L). Gα binds to GDP and associates with Gβγ. The heterotrimeric protein complex might associate with the receptor at this point, or remain free in the membrane as pictured. Upon ligand binding the GPCR becomes activated and undergoes a conformational change. The activated GPCR acts as a GEF for Gα. The resulting GTP-bound Gα separates from βγ, and the heterotrimeric proteins are active (*). Activated Gα can then interact with an effector (E), such as PLC or adenylate cyclase, which results in effector activation (*) and initiation of a second-messenger cascade. The GTP in Gα is then hydrolyzed to GDP through the activity of Gα and RGS proteins (not shown), leading to Gα inactivation and reassociation of the heterotrimeric protein complex. Independently, GRKs bind to and phosphorylate the GPCR. This stimulates its binding by β-arrestin (βArr), which promotes internalization of the receptor. The GPCR can then be recycled back to the cell surface without ligand, restarting the cycle.