title: Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization.
abstract: 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 Pro(353) 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.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Lan-Xue
authors.initials: LX
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S. E., Minneapolis, Minnesota, 55455, USA.
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S. E., Minneapolis, Minnesota, 55455, USA.
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D009154:Mutation; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism*
chemical_list: C485764:OPRM1 protein, human; D034741:RNA, Small Interfering; D017450:Receptors, Opioid, mu; D009020:Morphine; D000262:Adenylyl Cyclases; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus
keywords: Desensitization; FK506 binding protein 12; Internalization; Morphine; μ-Opioid receptor