Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization

• Published in: Neuroscience letters 2014-04, Vol.566, p.231-235
• Main Authors: Yan, Ying-Hui, Wang, Yan, Zhao, Lan-Xue, Jiang, Shan, Loh, Horace H., Law, Ping-Yee, Chen, Hong-Zhuan, Qiu, Yu
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Desensitization; FK506 binding protein 12; HEK293 Cells; Humans; Internalization; Morphine; Morphine - pharmacology; Mutation; Phosphorylation; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; RNA, Small Interfering - genetics; Tacrolimus - pharmacology; Tacrolimus Binding Protein 1A - genetics; Tacrolimus Binding Protein 1A - metabolism; μ-Opioid receptor
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2014.02.059

•OPRM1–FKBP12 interaction affects morphine-induced receptor internalization.•OPRM1–FKBP12 interaction affects morphine-induced adenylyl cyclase desensitization.•PPIase activity of FKBP12 may contribute to inhibition of receptor phosphorylation.•OPRM1–FKBP12 interaction may play a role in the development of morphine tolerance. Agonist-activated μ-opioid receptor (OPRM1) undergoes robust receptor phosphorylation by G protein-coupled receptor kinases and subsequent β-arrestin recruitment, triggering receptor internalization and desensitization. Morphine, a widely prescribed opioid, induces receptor phosphorylation inefficiently. Previously we reported that FK506 binding protein 12 (FKBP12) specifically interacts with OPRM1 and such interaction attenuates receptor phosphorylation and facilitates morphine-induced recruitment and activation of protein kinase C. In the current study, we demonstrated that the association of FKBP12 with OPRM1 also affects morphine-induced receptor internalization and G protein-dependent adenylyl cyclase desensitization. Morphine induced faster receptor internalization and adenylyl cyclase desensitization in cells expressing OPRM1 with Pro353 mutated to Ala (OPRM1P353A), which does not interact with FKBP12, or in the presence of FK506 which dissociates the receptor–FKBP12 interaction. Furthermore, knockdown of cellular FKBP12 level by siRNA accelerated morphine-induced receptor internalization and adenylyl cyclase desensitization. Our study further demonstrated that peptidyl prolyl cis–trans isomerase activity of FKBP12 probably plays a role in inhibition of receptor phosphorylation. In the view that internalized receptor recycles and thus counteracts the development of analgesic tolerance, receptor's association with FKBP12 could also contribute to the development of morphine tolerance through modulation of receptor trafficking.