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Agonist-Induced Internalization of Leukotriene B₄ Receptor 1 Requires G-Protein-Coupled Receptor Kinase 2 but Not Arrestins

Zhangguo Chen, Rémi Gaudreau, Christian Le Gouill, Marek Rola-Pleszczynski, and Jana Staková

Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

The leukotriene B₄ (LTB₄) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB₄ stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB₄, BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail–truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB₄, suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type–specific signaling in response to LTB₄, depending on GRK expression levels.

Address correspondence to: Jana Staková, Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, 3001 N. 12th Avenue, Sherbrooke, QC J1H 5N4, Canada. E-mail: jana.stankova{at}usherbrooke.ca

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