title: Serine 363 of the {delta}-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands.
abstract: Distinct opioid receptor agonists have been proved to induce differential patterns of ERK activation, but the underlying mechanisms remain unclear. Here, we report that Ser363 in the δ-opioid receptor (δOR) determines the different abilities of the δOR agonists DPDPE and TIPP to activate ERK by G-protein- or β-arrestin-dependent pathways. Although both DPDPE and TIPP activated ERK1/2, they showed different temporal, spatial and desensitization patterns of ERK activation. We show that that DPDPE employed G protein as the primary mediator to activate the ERK cascade in an Src-dependent manner, whereas TIPP mainly adopted a β-arrestin1/2-mediated pathway. Moreover, we found that DPDPE gained the capacity to adopt the β-arrestin1/2-mediated pathway upon Ser363 mutation, accompanied by the same pattern of ERK activation as that induced by TIPP. Additionally, we found that TIPP- but not DPDPE-activated ERK could phosphorylate G-protein-coupled receptor kinase-2 and β-arrestin1. However, such functional differences of ERK disappeared with the mutation of Ser363. Therefore, the present study reveals a crucial role for Ser363 in agonist-specific regulation of ERK activation patterns and functions.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Xu
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Hong
authors.forename: Le-Sha
authors.initials: LS
authors.lastname: Zhang
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Hou
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Wang
authors.forename: Yue-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chi
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D054799:Phospholipase C beta / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D008024:Ligands; D050505:Mutant Proteins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; D000071557:beta-Arrestins; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine; D012694:Serine; D020881:Enkephalin, D-Penicillamine (2,5)-; D016392:Proto-Oncogene Proteins pp60(c-src); D054769:G-Protein-Coupled Receptor Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054799:Phospholipase C beta