Regulation of G protein-coupled receptor endocytosis and trafficking by Rab GTPases.
G protein-coupled receptors (GPCRs) are integral membrane proteins that, in response to activation by extracellular stimuli, regulate intracellular second messenger levels via their coupling to heterotrimeric G proteins. GPCR activation also initiates a series of molecular events that leads to G protein-coupled receptor kinase-mediated receptor phosphorylation and the binding of beta-arrestin proteins to the intracellular face of the receptor. beta-Arrestin binding not only contributes to the G protein-uncoupling of GPCRs, but also mediates the targeting of many GPCRs for endocytosis in clathrin-coated pits. Several GPCRs internalize as a stable complex with beta-arrestin and the stability of this complex appears to regulate, at least in part, whether the receptors are dephosphorylated in early endosomes and recycled back to the cell surface as fully functional receptors, retained in early endosomes or targeted for degradation in lysosomes. More recently, it has become appreciated that the movement of GPCRs through functionally distinct intracellular membrane compartments is regulated by a variety of Rab GTPases and that the activity of these Rab GTPases may influence GPCR function. Moreover, it appears that GPCRs are not simply passive cargo molecules, but that GPCR activation may directly influence Rab GTPase activity and as such, GPCRs may directly control their own targeting between intracellular compartments. This review provides a synopsis of the current knowledge regarding the role of beta-arrestins and Rab GTPases in regulating the intracellular trafficking and function of GPCRs.
Seachrist
Jennifer L
JL
Cell Biology Research Group, Robarts Research Institute, 100 Perth Dr., N6A 5K8, London, Ontario, Canada.
Ferguson
Stephen S G
SS
D000818:Animals; D019390:Arrestins / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000071557:beta-Arrestins; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D020695:rab4 GTP-Binding Proteins / Q000502:physiology; D020696:rab5 GTP-Binding Proteins / Q000502:physiology; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D020691:rab GTP-Binding Proteins; D020695:rab4 GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins