Beta-arrestin-dependent mu-opioid receptor-activated extracellular signal-regulated kinases (ERKs) Translocate to Nucleus in Contrast to G protein-dependent ERK activation.
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 beta-arrestins resulted in the cytosolic retention of the phosphorylated ERKs. However, we observed distinct differences from this established ERKs cellular itinerary with the mu-opioid receptor-activated ERKs. Agonists such as morphine and methadone activated ERKs via the protein kinase C-dependent pathway but not the beta-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 beta-arrestin-dependent manner. The phosphorylated ERKs translocated into the nucleus, resulting in increases in Elk-1 activity and GRK2 and beta-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.
Zheng
Hui
H
Department of Pharmacology, Medical School, University of Minnesota. 6-120 Jackson Hall, 321 Church Street S.E., Minneapolis, MN 55455-0217, USA. zhen0091@umn.edu
Loh
Horace H
HH
Law
Ping-Yee
PY
D019390:Arrestins / Q000378:metabolism*; D001692:Biological Transport; D002467:Cell Nucleus / Q000201:enzymology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins