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

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...

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Published inThe EMBO journal Vol. 23; no. 16; pp. 3282 - 3289
Main Authors Schulz, Stefan, Mayer, Dana, Pfeiffer, Manuela, Stumm, Ralf, Koch, Thomas, Höllt, Volker
Format Journal Article
LanguageEnglish
Published England 18.08.2004
Subjects
Cell Line
Enkephalin, Ala-MePhe-Gly- - pharmacology
Humans
Morphine - pharmacology
Mutation - genetics
Phosphorylation - drug effects
Phosphoserine - metabolism
Receptors, Opioid, mu - genetics
Receptors, Opioid, mu - metabolism
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Summary: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).
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ISSN:0261-4189