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 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).
Schulz
Stefan
S
Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Magdeburg, Germany. stefan.schulz@medizin.uni-magdeburg.de
Mayer
Dana
D
Pfeiffer
Manuela
M
Stumm
Ralf
R
Koch
Thomas
T
Höllt
Volker
V
D002460:Cell Line; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*
D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D010768:Phosphoserine; D009020:Morphine