%0 Journal Article %A William T Birdsong %A Seksiri Arttamangkul %A James R Bunzow %A John T. Williams %T Agonist Binding and Desensitization of the Mu-Opioid Receptor Is Modulated By Phosphorylation of the C-Terminal Tail Domain %D 2015 %R 10.1124/mol.114.097527 %J Molecular Pharmacology %P mol.114.097527 %X Sustained activation of G protein-coupled receptors can lead to a rapid decline in signaling through acute receptor desensitization. In the case of the mu-opioid receptor (MOPr) this desensitization may play a role in the development of analgesic tolerance. It is understood that phosphorylation of MOPr promotes association with β-arrestin proteins, which then facilitates desensitization and receptor internalization. Agonists that induce acute desensitization have been shown to induce a non-canonical high-affinity agonist binging state in MOPr - conferring a persistent memory of prior receptor activation. In the current study, live-cell confocal imaging was used to investigate the role of receptor phosphorylation in agonist binding to MOPr. A phosphorylation cluster in the C-terminal tail of MOPr was identified as a mediator of agonist-induced affinity changes in MOPr. This site is unique from the primary phosphorylation cluster responsible for β-arrestin binding and internalization. Electrophysiological measurements of receptor function suggest that both phosphorylation clusters may play a parallel role during acute receptor desensitization. Desensitization was unaffected by alanine mutation of either phosphorylation cluster, but was largely eliminated when both clusters were mutated. Overall, this work suggests that there are multiple effects of MOPr phosphorylation that appear to regulate MOPr function, one affecting β-arrestin binding and a second affecting agonist binding. %U https://molpharm.aspetjournals.org/content/molpharm/early/2015/04/30/mol.114.097527.full.pdf