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Morphine and etorphine activate same G protein but exhibit distinct pathways in μ‐opioid receptor‐mediated ERK1/2 activation
Author(s) -
Zheng Hui,
Loh Horace H,
Law Pingyee
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.908.9
Subject(s) - etorphine , g protein coupled receptor , agonist , arrestin , g protein , microbiology and biotechnology , chemistry , signal transduction , receptor , opioid receptor , μ opioid receptor , protein kinase c , opioid , biology , biochemistry , (+) naloxone
G protein‐ and β‐arrestin‐dependent pathways are well established mechanisms in agonist‐selective signaling of GPCRs. Classically, GPCR signaled via G protein initially and then switched to β‐arrestin‐dependent signaling. Recently, different GPCR conformations induced by different agonists were suggested to determine the signaling pathway, suggesting ß‐arrestin can mediate signaling without G protein activation. In current study, we could demonstrate agonist‐selective signaling in μ‐opioid receptor (MOR)‐mediated ERK1/2 activation in both cell models and primary hippocampal neurons. Morphine and etorphine activated ERK1/2 via PKC and β‐arrestin respectively. In addition, morphine‐activated ERK1/2 stayed in cytosol while etorphine‐activated ERK1/2 translocated into nucleus. Most importantly, the ERK1/2 phosphorylations induced by both agonists were blocked by PTX and could be restored with the over‐expression of PTX‐insensitive Gi2α mutant. Thus, we concluded that the conformations of agonist‐receptor complexes resulting in the recruitment of different cellular proteins such as PKC or ß‐arrestin will determine the pathway selected for the eventual signals. (Research supported by NIDA grants)