Subcellular Organization of GPCR Signaling

G protein-coupled receptors (GPCRs) comprise a large and diverse class of signal-transducing receptors that undergo dynamic and isoform-specific membrane trafficking. GPCRs thus have an inherent potential to initiate or regulate signaling reactions from multiple membrane locations. This review discusses emerging insights into the subcellular organization of GPCR function in mammalian cells, focusing on signaling transduced by heterotrimeric G proteins and β-arrestins. We summarize recent evidence indicating that GPCR-mediated activation of G proteins occurs not only from the plasma membrane (PM) but also from endosomes and Golgi membranes and that β-arrestin-dependent signaling can be transduced from the PM by β-arrestin trafficking to clathrin-coated pits (CCPs) after dissociation from a ligand-activated GPCR. Active signal initiation by GPCRs is not restricted to the PM. GPCR-mediated activation of Gs can occur in endosomes and the Golgi apparatus. β-Arrestin-mediated activation of MAP kinase can occur from the PM. β-Arrestin can mediate signaling after dissociating from its activating GPCR. Clathrin-coated pits function as β-arrestin signaling stations in the PM.