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PMID: 15272312 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Morphine induces terminal micro-opioid receptor desensitization by sustained phosphorylation of serine-375.

The EMBO journal ·Vol. 23 ·No. 16 ·2004-08-18 ·Pages 3282-9

Schulz S, Mayer D, Pfeiffer M, Stumm R, Koch T, Höllt V

Abstract

Morphine is a poor inducer of micro-opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [D-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy-terminal residue 375 (Ser(375)). Ser(375) phosphorylation was sufficient and required for morphine-induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO-desensitized receptors were rapidly dephosphorylated. In contrast, morphine-desensitized receptors remained at the plasma membrane in a Ser(375)-phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser(375).

MeSH Terms
Cell Line Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology Humans Morphine/pharmacology Mutation/genetics Phosphorylation/drug effects Phosphoserine/metabolism Receptors, Opioid, mu/genetics,metabolism
Chemicals
Receptors, Opioid, mu Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Phosphoserine Morphine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Schulz Stefan
Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Magdeburg, Germany. stefan.schulz@medizin.uni-magdeburg.de
Mayer Dana
Pfeiffer Manuela
Stumm Ralf
Koch Thomas
Höllt Volker
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600334
Email
stefan.schulz@medizin.uni-magdeburg.de
Published
2004-08-18
Epub
2004-00-22
Pages
3282-9
Language
English
Region
England
NLM ID
8208664
PMCID
PMC514508
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600334 PMC Full Text View journal details
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