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Originally published In Press as doi:10.1074/jbc.M101535200 on July 16, 2001

J. Biol. Chem., Vol. 276, Issue 36, 33847-33853, September 7, 2001
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µ-Opioid Receptor-mediated ERK Activation Involves Calmodulin-dependent Epidermal Growth Factor Receptor Transactivation*

Mariana M. BelchevaDagger , Maria SzùcsDagger §, Danxin Wang, Wolfgang Sadee, and Carmine J. CosciaDagger ||

From the Dagger  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

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.

* 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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