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Morphine induces terminal μ‐opioid receptor desensitization by sustained phosphorylation of serine‐375
Author(s) -
Schulz Stefan,
Mayer Dana,
Pfeiffer Manuela,
Stumm Ralf,
Koch Thomas,
Höllt Volker
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600334
Subject(s) - humanities , philosophy
Morphine is a poor inducer of μ‐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 .