RT Journal Article
SR Electronic
T1 Different effects of the different natural CC-chemokine receptor 2B (CCR2B) ligands on β-arrestin recruitment, Gαi signalling, and receptor internalization
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.068486
DO 10.1124/mol.110.068486
A1 Yamina A. Berchiche
A1 Stephanie Gravel
A1 Marie-Eve Pelletier
A1 Genevieve St-Onge
A1 Nikolaus Heveker
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/11/18/mol.110.068486.abstract
AB The chemokine receptor CCR2, which has been implicated in a variety of inflammatory, auto-immune and cardiovascular conditions, binds several natural chemokine ligands. Here, we assessed the recruitment of β-arrestin to CCR2 in response to these ligands using Bioluminescence Resonance Energy Transfer (BRET) technology. Compared to CCL2, which was considered as a full agonist, other CCR2 ligands were partial agonists with reduced efficacy and potency. Agonist potencies were not a function of their affinity for CCR2. Efficacy of arrestin recruitment matched that of agonist-induced CCR2 internalization. Although the potency and efficacy rank orders of the ligands in arrestin recruitment were similar to those observed for Gαi1 activation, arrestin recruitment was at least in part resistant to Gαi/o-inactivating pertussis toxin, suggesting partial independence from Gαi/o. The degree of pertussis toxin resistance of arrestin recruitment was different between the chemokines. Moreover, qualitative differences between the arrestin responses to the different ligands were identified in the stability of the response: while CCL7-induced arrestin recruitment had a half-life of less than 15 minutes, CCL8 and CCL13 induced stable CCR2-arrestin interactions. Finally, the ligands stabilized different conformations of the CCR2 homodimer. Our results support the validity of models for receptor-ligands interactions in which different ligands stabilize different receptor conformations also for endogenous receptor ligands, with corresponding implications for drug development targeting CCR2.