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J. Biol. Chem., Vol. 277, Issue 35, 31567-31576, August 30, 2002
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From the Immunology Division, Department of Pediatrics, Faculty of
Medicine, Université de Sherbrooke,
Sherbrooke, Quebec J1H 5N4, Canada
Desensitization of G-protein-coupled
receptors may involve phosphorylation of serine and threonine
residues. The leukotriene B4 (LTB4)
receptor (BLT1) contains 14 intracellular serines and threonines, 8 of
which are part of consensus target sequences for protein kinase C (PKC)
or casein kinase 2. In this study, we investigated the importance of
PKC and GPCR-specific kinase (GRK) phosphorylation in BLT1
desensitization. Pretreatment of BLT1-transfected COS-7 cells with PKC
activators caused a decrease of LTB4-induced inositol
phosphate (IP) accumulation. This reduction was prevented with the PKC
inhibitor, staurosporine, and not observed in cells expressing a BLT1
deletion mutant (G291stop) lacking the cytoplasmic tail. Moreover
LTB4-induced IP accumulation was significantly inhibited by
overexpression of GRK2, GRK5, and especially GRK6, in cells expressing
wild type BLT1 but not in those expressing G291stop. GRK6-mediated
desensitization correlated with increased phosphorylation of BLT1. The
G319stop truncated BLT1 mutant displayed functional characteristics
comparable with wild type BLT1 in terms of desensitization by GRK6, but
not by PKC. Substitution of Thr308 within a putative casein
kinase 2 site to proline or alanine in the full-length BLT1 receptor
prevented most of GRK6-mediated inhibition of LTB4-induced
IP production but only partially affected LTB4-induced BLT1
phosphorylation. Our findings thus suggest that Thr308 is a
major residue involved in GRK6-mediated desensitization of BLT1 signaling.
Threonine 308 within a Putative Casein Kinase 2 Site of the
Cytoplasmic Tail of Leukotriene B4 Receptor (BLT1) Is
Crucial for Ligand-induced, G-protein-coupled Receptor-specific
Kinase 6-mediated Desensitization*
*
This work was supported by the Medical Research Council of
Canada and by a Studentship from the Fonds pour les Chercheurs et
l'Aide à la Recherche (to R. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Immunology Division,
Dept. of Pediatrics, Faculty of Medicine, Université de Sherbrooke, 3001 N. 12th Ave., Sherbrooke, Quebec J1H 5N4, Canada. Tel.: 819-346-1110 (ext. 14851); Fax: 819-564-5215; E-mail:
mrolaple@courrier.usherb.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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