Figure 5.

GPCR trafficking and compartmentalized signaling. The formation of GPCR-mediated signaling platforms provides a mechanism to sculpt specific cellular responses. (1) GPCRs at the plasma membrane form multiprotein complexes that participate in the regulation of a specific signaling pathway (pathway A). For example, AKAP interactions with GPCRs can scaffold the formation of complexes that regulate cAMP signaling by bringing in close proximity enzymes that degrade cAMP (PDEs) and kinases that are activated by this second messenger (PKA). (2) With prolonged agonist stimulation, GPCRs are phosphorylated by GRKs. The phosphorylated receptor has higher affinity for the cytosolic protein ARRB. (3) ARRBs are adaptors that promote clathrin-and dynamin-mediated endocytosis of GPCRs. (4) ARRBs scaffold the formation of multi-protein complexes that result in a second wave of intracellular signaling (pathway B). Genetically encoded biosensors have shown differences in the spatial and temporal profile of GPCR signaling from different subcellular locations (insets). AKAP, A-kinase anchor protein; GRK, G-protein receptor kinase; PDE, phosphodiesterase; PKA, protein kinase A.