期刊
EMBO JOURNAL
卷 23, 期 16, 页码 3282-3289出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7600334
关键词
desensitization; morphine; opioid receptor; phosphorylation; tolerance
Morphine is a poor inducer of mu-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 carboxyterminal 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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