Studies over the last two decades have firmly cemented the notion that G protein-coupled receptors (GPCRs) can signal from a variety of intracellular membranes, not just the cell surface. In as much as GPCRs maintain and regulate cellular responses to a wide range of external stimuli, it makes sense that these master regulators also play critical roles within cells coordinating the complex spatial and temporal interactions required for maintenance and function. Current data indicate andgt;120 GPCRs can signal from intracellular membranes including the nucleus, various endosomal vesicles as well as the trans-Golgi network (TGN), the Golgi, endoplasmic reticulum (ER), and even mitochondria and lysosomes. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated in situ via de novo ligand synthesis, diffusion of permeable ligands, or active transport of nonpermeable ligands. The wealth of data demonstrating intracellular GPCRs playing a dynamic role in a host of biological functions including learning and memory, contractility, pain, angiogenesis, and cancer opens the door for new pharmacological opportunities and the development of more effective therapeutic tools. Further in-depth study of compartmentalized signaling and associated drug discovery studies will provide valuable insights and new location-specific drug targets.

Original languageEnglish
Title of host publicationGPCRs as Therapeutic Targets
Number of pages83
ISBN (Electronic)9781119564782
ISBN (Print)9781119564744
StatePublished - Jan 1 2021


  • G protein-coupled receptor
  • endosome
  • intracellular
  • intracrine signaling
  • nucleoplasmic reticulum
  • nucleus
  • β-arrestin


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