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J. Biol. Chem., Vol. 276, Issue 36, 33847-33853, September 7, 2001
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From the Phosphorylation of the MAPK isoform ERK by G
protein-coupled receptors involves multiple signaling pathways.
One of these pathways entails growth factor receptor transactivation
followed by ERK activation. This study demonstrates that a similar
signaling pathway is used by the µ-opioid receptor (MOR) expressed in
HEK293 cells and involves calmodulin (CaM). Stimulation of MOR resulted in both epidermal growth factor receptor (EGFR) and ERK
phosphorylation. Data obtained with inhibitors of EGFR Tyr kinase and
membrane metalloproteases support an intermediate role of EGFR
activation, involving release of endogenous membrane-bound epidermal
growth factor. Previous studies had demonstrated a role for CaM in
opioid signaling based on direct CaM binding to MOR. To test whether CaM contributes to EGFR transactivation and ERK phosphorylation by MOR,
we compared wild-type MOR with mutant K273A MOR, which binds CaM
poorly, but couples normally to G proteins. Stimulation of K273A MOR
with
[D-Ala2,MePhe4,Gly-ol5]enkephalin
(10-100 nM) resulted in significantly reduced ERK phosphorylation. Furthermore, wild-type MOR stimulated EGFR Tyr phosphorylation 3-fold more than K273A MOR, indicating that direct CaM-MOR interaction plays a key role in the transactivation process. Inhibitors of CaM and protein kinase C also attenuated
[D-Ala2,MePhe4,Gly-ol5]enkephalin-induced
EGFR transactivation in wild-type (but not mutant) MOR-expressing
cells. This novel pathway of EGFR transactivation may be shared by
other G protein-coupled receptors shown to interact with
CaM.
µ-Opioid Receptor-mediated ERK Activation Involves
Calmodulin-dependent Epidermal Growth Factor Receptor
Transactivation*
,§,
Department Biochemistry and Molecular
Biology, St. Louis University School of Medicine, St. Louis, Missouri
63104, the § Biological Research Center, Hungarian Academy
of Sciences, Szeged, H-6701 Hungary, and the ¶ Department
of Biopharmaceutical Science and Pharmaceutical Chemistry,
University of California, San Francisco, California 94143
*
This work was supported in part by Research Grants DA05412
(to C. J. C.) and DA04166 (to W. S.) from the National Institute on
Drug Abuse, Research Grant OTKA T-033062 (to M. S.) from the Hungarian
Research Fund, Research Grant JFNo-564 (to M. S. and C. J. C.) from
the United States-Hungarian Joint Fund, and National Institute of
General Medical Sciences Research Grant GM43102 (to W. S.) from the
National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
314-577-8160; Fax: 314-577-8156; E-mail: cosciacc@slu.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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