Modulation of mTOR Activity by μ‐Opioid Receptor is Dependent upon the Association of Receptor and FK506‐Binding Protein 12

• Published in: CNS neuroscience & therapeutics Vol. 21; no. 7; pp. 591 - 598
• Main Authors: Wang, Yan, Ge, Yan‐Hui, Wang, Yan‐Xia, Liu, Ting, Law, Ping‐Yee, Loh, Horace H., Chen, Hong‐Zhuan, Qiu, Yu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2015; John Wiley and Sons Inc
• Subjects: Analgesics, Opioid - pharmacology; FK506‐binding protein 12; HEK293 Cells; Humans; Immunoprecipitation; Mechanistic/mammalian target of rapamycin; Morphine - pharmacology; Original; Protein interaction; Receptors, Opioid, mu - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Tacrolimus Binding Protein 1A - metabolism; TOR Serine-Threonine Kinases - metabolism; Transfection; μ‐opioid receptor; FK506-binding protein 12; Mechanistic/mammalian target of rapamycin; Protein interaction; μ-opioid receptor
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12409

Summary Aims Mechanistic/mammalian target of rapamycin (mTOR) activation by μ‐opioid receptor (OPRM1) participates in antinociceptive tolerance, hyperalgesia, and physical dependence. Our previous study also showed that mTOR activation by OPRM1 could attenuate β amyloid oligomers‐induced neurotoxicity. OPRM1 is demonstrated to interact with FK506‐binding protein 12 (FKBP12). It is our great interest to investigate whether OPRM1‐mediated mTOR signaling is related to receptor‐FKBP12 association. Methods The activities of mTOR and its downstream effector p70 S6K were measured by immunoblotting their phosphorylation status. The interaction of receptor with mTOR was detected by co‐immunoprecipitation and immunofluorescence. Results OPRM1 activation by morphine‐induced time‐dependent mTOR activation. PI3K‐specific inhibitor LY294002 only blocked the late phase of mTOR activation. However, morphine‐induced mTOR activation was totally blocked at all time points in cells expressing FKBP12 association‐deficient mutant receptor. FKBP12 knockdown also blocked morphine‐induced mTOR activation. Further analysis demonstrated that morphine treatment enhanced the association of receptor with phosphorylated mTOR, whereas decreased association was observed after FKBP12 knockdown, mTOR inhibition or in cells expressing FKBP12 association‐deficient mutant. Conclusions OPRM1‐FKBP12 association played a key role in OPRM1‐mediated mTOR activation, which could underlie the mechanisms of multiple physiological and pathological processes. Thus, our findings provide new avenue to modulating these processes.