RT Journal Article SR Electronic T1 Homologous Regulation of Mu Opioid Receptor Recycling by Gβγ, Protein Kinase C, and Receptor Phosphorylation JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 702 OP 710 DO 10.1124/mol.119.117267 VO 96 IS 6 A1 Jennifer M. Kunselman A1 Amanda S. Zajac A1 Zara Y. Weinberg A1 Manojkumar A. Puthenveedu YR 2019 UL http://molpharm.aspetjournals.org/content/96/6/702.abstract AB 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 postendocytic 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, whereas activation of Gβγ increased recycling even after agonist removal. Phosphorylation 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 postendocytic trafficking of G protein–coupled receptors.SIGNIFICANCE STATEMENT G protein–coupled receptor (GPCR) localization in the endosome is being increasingly recognized as an important and distinct component of GPCR signaling and physiology. This study identifies a G protein–dependent and protein kinase C–dependent signaling pathway that dynamically regulates the endosomal localization 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.