Editors' ChoiceReceptors

Secretly Signaling

Sci. Signal.  19 Jan 2010:
Vol. 3, Issue 105, pp. ec18
DOI: 10.1126/scisignal.3105ec18

Association of seven-transmembrane receptors (7TMRs) with heterotrimeric guanine nucleotide–binding proteins (G proteins) is so common and so well established that the term “G protein–coupled receptor” (GPCR) is often used interchangeably with 7TMR to refer to this class of proteins. Ligand binding to 7TMRs also stimulates recruitment of β-arrestins, which terminate 7TMR signaling through G proteins and also mediate distinct signaling pathways. Some 7TMR fail to activate G protein signaling pathways; these are thought to act as co-receptors or as decoy receptors that scavenge ligand. Noting that ligand elicits β-arrestin binding for one such “decoy” receptor, CXCR7, Rajagopal et al. explored the possibility that CXCR7 might signal through β-arrestin despite its inability to mediate G protein signaling. Treatment of human embryonic kidney (HEK) 293 cells transiently transfected with plasmids encoding CXCR7 and fluorescently labeled β-arrestin2 with the CXCR7 ligands stromal-derived factor 1α (SDF-1α) or interferon-inducible T cell α chemoattractant (ITAC) stimulated β-arrestin2 recruitment to the plasma membrane. The two ligands elicited distinct spatiotemporal patterns of β-arrestin2 recruitment, with β-arrestin2 localizing to cytoplasmic vesicles 10 minutes after treatment of cells with SDF-1α but remaining associated with the membrane in cells treated with ITAC, patterns echoed by ligand-dependent extracellular signal–regulated kinase (ERK1/2) phosphorylation. In rat vascular smooth muscle cells (rVSMCs), which express CXCR7 mRNA and protein, the radioligand binding profile was characteristic of chemokine binding to CXCR7, and ITAC failed to activate Gαi or to elicit increases in intracellular calcium associated with Gαq activation. ITAC promoted rVSMC migration; migration was markedly reduced by β-arrestin2 knockdown and was inhibited by a CXCR7 antagonist. The authors thus conclude that CXCR7 mediates ligand-induced signaling through β-arrestin even in the absence of G protein signaling.

S. Rajagopal, J. Kim, S. Ahn, S. Craig, C. M. Lam, N. P. Gerard, C. Gerard, R. J. Lefkowitz, β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc. Natl. Acad. Sci. U.S.A. 107, 628–632 (2010). [Abstract] [Full Text]