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

• Autores: Stefan Schulz, Dana Mayer, Manuela Pfeiffer
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Nº. 16, 2004, págs. 3282-3289
• Idioma: inglés
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• Resumen

  • 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-Ala2-MePhe4-Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy-terminal residue 375 (Ser375). Ser375 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 Ser375-phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser375.