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Vol. 293, Issue 1, 237-247, April 2000
-Opioid Receptor Are
Dependent on a Phosphorylation-Dephosphorylation Mechanism
Laboratoire des Neurosciences, CNRS UMR 6551, Caen, France (A.H.,
S.A., J.P., P.J.); Laboratoire de Cancérologie
Expérimentale, Centre François Baclesse, Caen, France
(F.S.); Département des Récepteurs et Protéines
Membranaires, CNRS URA 9050, Illkirch Grafenstaden, France (L.S.,
D.M.); and Laboratoire d'Histologie-Biologie Cellulaire, Faculté
de Mèdecine, Caen, France (G.L.)
Internalization, recycling, and resensitization of the human 
-opioid
receptor (hDOR) were studied in the neuroblastoma cell line SK-N-BE,
endogenously expressing this receptor. Conventional and confocal
fluorescence microscopy observations, corroborated by Scatchard
analysis, indicated that after a 100 nM Eto treatment, 60 to 70% of
hDOR were rapidly internalized
(t1/2 < 15 min). This agonist-triggered internalization was reversible for a treatment not
exceeding 1 h and became irreversible for prolonged treatment (4 h), leading probably to the degradation and/or down-regulation of the
receptor. The rapid internalization of hDOR was totally blocked in the
presence of heparin, known as an inhibitor of G protein-coupled
receptor kinases (Benovic et al., 1989), a result indicating that
phosphorylation by these kinases is a critical step in desensitization
(Hasbi et al., 1998) and internalization of hDOR (present study) in
SK-N-BE cell line. Blockade of internalization by agents not
interferring with phosphorylation, as hypertonic sucrose or
concanavalin A, also blocked the resensitization (receptor functional
recovering) process. Furthermore, blockade of dephosphorylation of the
internalized hDOR by okadaic acid totally suppressed its recycling to
the plasma membrane and its subsequent resensitization. These results
indicate that regulatory events leading to desensitization, internalization, and recycling in a functional state of hDOR involve phosphorylation by a G protein-coupled receptor kinase, internalization via clathrin-coated vesicles, and dephosphorylation by acid phosphatases.
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