Figure 8.

Model depicting the redistribution and endosomal signaling of Gβγ. GPCR activation induces the dissociation of heterotrimeric G proteins into Gα and Gβγ subunits. The liberated Gβγ heterodimer activates its effectors such as PI3-kinase-γ at the plasma membrane, leading to the activation of AKT (1). Gβγ also interacts with Rab11a, promoting Gβγ trafficking to early and slowly recycling endosomes (as defined by the presence of Rab11a) (2). The assembly of a signaling complex occurs at endosomes after recruitment of PI3-kinase-γ followed by activation of AKT (steps 3 and 4). A fraction of AKT is associated with this endosomal fraction even in nonstimulated cells, but the association of this protein is further increased in response to receptor stimulation leading to the phosphorylation of endosomal AKT (5). GSK-3-β is recruited in response to receptor stimulation (step 6). Inhibition of PI3-kinase by Wm prevents the association of PI3-kinase-γ to endosomes and the phosphorylation of AKT. To complete the cycle, presumably Gβγ is recycled to the plasma membrane to start a new cycle of signaling (7).