@article {Kunselmanmol.119.117267, author = {Jennifer M Kunselman and Amanda S Zajac and Zara Y Weinberg and Manojkumar A Puthenveedu}, title = {Homologous regulation of mu opioid receptor recycling by Gβγ, Protein Kinase C, and receptor phosphorylation}, elocation-id = {mol.119.117267}, year = {2019}, doi = {10.1124/mol.119.117267}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Membrane trafficking and receptor signaling are two fundamental cellular processes that interact constantly. Although how trafficking regulates signaling is well studied, how signaling pathways regulate trafficking is less well understood. Here we use the mu opioid receptor (MOR), the primary target for opioid analgesics, to define a signaling pathway that dynamically regulates post-endocytic receptor recycling. By directly visualizing individual MOR recycling events, we show that agonist increases MOR recycling. Inhibition of Gβγ, Phospholipase-C, or Protein Kinase C mimicked agonist removal, while activation of Gβγ increased recycling even after agonist removal. Phosphoylation of serine 363 on the C-terminal tail of MOR was required and sufficient for agonist-mediated regulation of MOR recycling. Our results identify a feedback loop that regulates MOR recycling via Gβγ, Protein Kinase C, and receptor phosphorylation. This could serve as a general model for how signaling regulates post-endocytic trafficking of G protein-coupled receptors.SIGNIFICANCE STATEMENT GPCR dynamics in the endosome is being increasingly recognized as an important and distinct component of GPCR signaling and physiology. This study identifies a G-protein- and Protein Kinase C-dependent signaling pathway that dynamically regulates the endosomal sorting of the mu opioid receptor, the primary target of opioid analgesics and abused drugs. This pathway could provide a mechanism to manipulate spatial encoding of opioid signaling and physiology.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2019/10/01/mol.119.117267}, eprint = {https://molpharm.aspetjournals.org/content/early/2019/10/01/mol.119.117267.full.pdf}, journal = {Molecular Pharmacology} }