A novel noncanonicalsignaling pathway for the μ-opioid receptor

Author(s): Zhang L, Loh HH, Law PY


The µ-opioid receptor (OPRM1) signals as a classic G protein-coupled receptor by activating heterotrimeric Gi/Go proteins resulting in adenylyl cyclase (AC) inhibition. Such AC inhibition is desensitized after prolonged agonist treatment. However, after receptor desensitization, the intracellular cAMP level remains regulated by OPRM1, as demonstrated by the intracellular cAMP level increase or AC superactivation upon removal of an agonist or addition of an antagonist. We now demonstrate that such intracellular cAMP regulation is mediated by a novel noncanonical signaling pathway resulting from OPRM1 being converted to a receptor tyrosine kinase (RTK)-like entity. This noncanonical OPRM1 signaling is initiated by the receptor recruiting and activating Src kinase within the receptor complex, leading to phosphorylation of the OPRM1 Tyr(336) residue. Phospho-Tyr(336) serves as the docking site for growth factor receptor-bound protein/son of sevenless, leading to the recruitment and activation of the Ras/Raf-1 and subsequent phosphorylation and activation of AC5/6 by Raf-1. Such sequence of events was established by the absence of Ras/Raf1 recruitment and activation by the OPRM1-Y336F mutant, by the presence of Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) or the absence of Src activity, by the presence of specific Raf-1 inhibitor GW5074 (5-iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone) or the absence of Raf-1, or by the dominant negative RasN17 mutant. Src together with Ras activates Raf1 which was established by the inability of the Raf1-Tyr(340/341) mutant to activate AC. Hence, the phosphorylation of OPRM1 at Tyr(336) by Src serves as the trigger for the conversion of a classic Gi/Go-coupled receptor into an RTK-like entity, resulting in a noncanonical pathway even after the original Gi/Go signals are blunted.

Similar Articles

Enhanced morphine analgesia in mice lacking beta-arrestin 2

Author(s): Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, et al.

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence

Author(s): Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG, et al.

Ligand-directed signalling within the opioid receptor family

Author(s): Pradhan AA, Smith ML, Kieffer BL, Evans CJ

μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization

Author(s): McPherson J, Rivero G, Baptist M, Llorente J, Al-Sabah S, et al.

Morphine-like opiates selectively antagonize receptor-arrestin interactions

Author(s): Molinari P, Vezzi V, Sbraccia M, Grò C, Riitano D, et al.

Pharmacological characterization of AR-M1000390 at human delta opioid receptors

Author(s): Marie N, Landemore G, Debout C, Jauzac P, Allouche S

SK-N-BE: a human neuroblastoma cell line containing two subtypes of delta-opioid receptors

Author(s): Polastron J, Mur M, Mazarguil H, Puget A, Meunier JC, et al.

ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands

Author(s): Aguila B, Coulbault L, Davis A, Marie N, Hasbi A, et al.

Molecular control of δ-opioid receptor signalling

Author(s): Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA, et al.

Development and validation of a genetic algorithm for flexible docking

Author(s): Jones G, Willett P, Glen RC, Leach AR, Taylor R, et al.

Agonist-selective mechanisms of GPCR desensitization

Author(s): Kelly E, Bailey CP, Henderson G

Recovery from mu-opioid receptor desensitization after chronic treatment with morphine and methadone

Author(s): Quillinan N, Lau EK, Virk M, von Zastrow M, Williams JT

Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes

Author(s): Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, et al.