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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arrestins / metabolism
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Cytoplasm / drug effects
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Cytoplasm / enzymology
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Enkephalin, D-Penicillamine (2,5)- / pharmacology
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Enzyme Activation / drug effects
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G-Protein-Coupled Receptor Kinase 2 / metabolism
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GTP-Binding Protein beta Subunits / metabolism
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GTP-Binding Protein gamma Subunits / metabolism
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Ligands
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MAP Kinase Signaling System* / drug effects
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Mutant Proteins / metabolism
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Mutation / genetics
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Oligopeptides / pharmacology
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Phospholipase C beta / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Receptors, Opioid, delta / metabolism*
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Serine / metabolism*
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Structure-Activity Relationship
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
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Tetrahydroisoquinolines / pharmacology
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beta-Arrestins
Substances
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Arrestins
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GTP-Binding Protein beta Subunits
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GTP-Binding Protein gamma Subunits
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Ligands
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Mutant Proteins
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Oligopeptides
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Receptors, Opioid, delta
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Tetrahydroisoquinolines
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beta-Arrestins
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tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine
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Serine
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Enkephalin, D-Penicillamine (2,5)-
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Proto-Oncogene Proteins pp60(c-src)
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G-Protein-Coupled Receptor Kinase 2
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Phospholipase C beta