Homologous regulation of mu opioid receptor recycling by Gβγ, protein kinase C, and receptor phosphorylation

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 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.