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Molecular Pharmacology

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Research ArticleArticle

β-Arrestin-Dependent μ-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation

Hui Zheng, Horace H. Loh and Ping-Yee Law
Molecular Pharmacology January 2008, 73 (1) 178-190; DOI: https://doi.org/10.1124/mol.107.039842
Hui Zheng
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Horace H. Loh
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Ping-Yee Law
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Abstract

The cellular location of extracellular signal-regulated kinases (ERKs) activated by a G protein-coupled receptor was shown to be dependent on the pathway that mediated their activation. In general, fast activation of ERKs (2 min) mediated by G proteins resulted in the nuclear translocation of phosphorylated ERKs, whereas a slower activation of ERKs (10 min) mediated by β-arrestins resulted in the cytosolic retention of the phosphorylated ERKs. However, we observed distinct differences from this established ERKs cellular itinerary with the μ-opioid receptor-activated ERKs. Agonists such as morphine and methadone activated ERKs via the protein kinase C-dependent pathway but not the β-arrestin-dependent pathway. The activated ERKs did not translocate into the nucleus, but phosphorylated 90-kDa ribosomal S6 kinase and induced the activity of transcription factor cAMP response element-binding protein. In contrast, agonists such as etorphine and fentanyl activated ERKs in a β-arrestin-dependent manner. The phosphorylated ERKs translocated into the nucleus, resulting in increases in Elk-1 activity and GRK2 and β-arrestin2 transcriptions. Thus, the cellular location of phosphorylated ERKs and subsequent activities on gene transcriptions are dictated by the agonist used to activate the receptor and the subsequent signaling pathway involved.

Footnotes

  • This research was supported in part by National Institutes of Health grants DA007339, DA016674, DA000564, and DA011806. H.H.L. and P.Y.L. are recipients of K05-DA70544 and K05-DA00513, respectively.

  • ABBREVIATIONS: ERK, extracellular signal-regulated kinase; 90RSK, 90-kDa ribosomal s6 kinase; CREB, cAMP response element-binding; GPCR, G protein-coupled receptor; HEK, human embryonic kidney; MEF, mouse embryonic fibroblast; MOR, μ-opioid receptor; PKC, protein kinase C; HA, hemagglutinin; FBS, fetal bovine serum; FACS, fluorescence-activated cell sorting; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; MEK, mitogen-activated protein kinase kinase; DOR, δ-opioid receptor; CTOP, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2; DAMGO, [d-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin; ICI118551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; Ro-31-8425, 2-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methylindol-3-yl)maleimide, HCl; PD98059, 2′-amino-3′-methoxyflavone; HA-MOR, hemagglutinin-tagged μ-opioid receptor; TIPPψ, H-Tyr-Ticψ[CH2NH]-Phe-Phe-OH.

    • Received July 16, 2007.
    • Accepted October 18, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (1)
Molecular Pharmacology
Vol. 73, Issue 1
1 Jan 2008
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Research ArticleArticle

β-Arrestin-Dependent μ-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation

Hui Zheng, Horace H. Loh and Ping-Yee Law
Molecular Pharmacology January 1, 2008, 73 (1) 178-190; DOI: https://doi.org/10.1124/mol.107.039842

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Research ArticleArticle

β-Arrestin-Dependent μ-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation

Hui Zheng, Horace H. Loh and Ping-Yee Law
Molecular Pharmacology January 1, 2008, 73 (1) 178-190; DOI: https://doi.org/10.1124/mol.107.039842
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