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

Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, Minnesota

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.

Address correspondence to: Dr. Hui Zheng, Department of Pharmacology, Medical School, University of Minnesota. 6-120 Jackson Hall, 321 Church Street S.E., Minneapolis, MN 55455-0217. E-mail: zhen0091{at}umn.edu

This article has been cited by other articles:

				H. Zheng, J. Chu, Y. Qiu, H. H. Loh, and P.-Y. Law Agonist-selective signaling is determined by the receptor location within the membrane domains PNAS, July 8, 2008; 105(27): 9421 - 9426. [Abstract] [Full Text] [PDF]