Regulation of G protein‐coupled receptor signaling by plasma membrane organization and endocytosis

The trafficking of G protein coupled‐receptors (GPCRs) is one of the most exciting areas in cell biology because of recent advances demonstrating that GPCR signaling is spatially encoded. GPCRs, acting in a diverse array of physiological systems, can have differential signaling consequences depending on their subcellular localization. At the plasma membrane, GPCR organization could fine‐tune the initial stages of receptor signaling by determining the magnitude of signaling and the type of effectors to which receptors can couple. This organization is mediated by the lipid composition of the plasma membrane, receptor‐receptor interactions, and receptor interactions with intracellular scaffolding proteins. GPCR organization is subsequently changed by ligand binding and the regulated endocytosis of these receptors. Activated GPCRs can modulate the dynamics of their own endocytosis through changing clathrin‐coated pit dynamics, and through the scaffolding adaptor protein β‐arrestin. This endocytic regulation has signaling consequences, predominantly through modulation of the MAPK cascade. This review explores what is known about receptor sorting at the plasma membrane, protein partners that control receptor endocytosis, and the ways in which receptor sorting at the plasma membrane regulates downstream trafficking and signaling. G protein‐coupled receptors (GPCRs) have long been known to signal from the plasma membrane via multiple signaling pathways. GPCR organization at the plasma membrane plays a critical role in regulating the signaling consequences of receptor activation by regulating the interactions of receptors with specific effector proteins. GPCR organization can be regulated by dynamic association with proteins and membrane microdomains. Furthermore, GPCRs also regulate their own endocytic rate in a ligand‐ and receptor‐dependent manner, with consequences for receptor signaling. This review explores our current understanding of basal organization of GPCRs in the plasma membrane and the functional consequences of this organization on GPCR endocytosis and signaling.