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Vol. 55, Issue 2, 263-268, February 1999
Department of Pharmacology and Toxicology (R.W., T.K., S.S., M.K.,
H.S., E.R., V.H.) and
Department of Immunology (F.B.),
Otto-von-Guericke University, Magdeburg, Germany
Signaling of G protein-coupled receptors is terminated by
phosphorylation of intracellular serine and threonine residues. Resensitization of these receptors requires internalization and subsequent dephosphorylation. We have recently shown that the resensitization rate of the rat µ opioid receptor (MOR) isoforms MOR1
and MOR1B is mainly determined by the amino acid composition of their
alternatively spliced C-terminal tails. Upon agonist stimulation, MOR1B
passes through an accelerated cycle of receptor endocytosis and
reactivation, which in turn promotes a greater resistance to
agonist-induced desensitization, as compared with MOR1. Given the fact
that MOR1B lacks only one putative phosphorylation site (T394 of MOR1),
we replaced this threonine by an alanine and stably expressed the
wild-type MOR1 and its T394A mutant in mouse neuroblastoma Neuro2a
cells. We show that during prolonged [D-Ala2, MePhe4,
Gly5-ol]enkephalin exposure (5 h), the T394A
receptor mutant desensitized at a slower rate than MOR1. In contrast,
T394A is more rapidly removed from the cell surface than MOR1, as
determined by flow cytometry using epitope-tagged receptors. This fast
internalization was followed by immediate resensitization of T394A
during 20 min of agonist removal while the wild-type MOR1 remained
inactive. Similar to MOR1B, rapid internalization and reactivation of
T394A may explain its delayed desensitization. These findings suggest that T394 represents a negative regulatory signal for MOR1
internalization. Furthermore, phosphorylation of this threonine residue
may influence the time course of µ opioid receptor resensitization.
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