CXCR7 is an atypical
chemokine receptor that signals through β-
arrestin in response to agonists without detectable activation of
heterotrimeric G-proteins. Its cognate
chemokine ligand CXCL12 also binds CXCR4, a
chemokine receptor of considerable clinical interest. Here we report that
TC14012, a
peptidomimetic inverse agonist of CXCR4, is an agonist on CXCR7. The potency of β-
arrestin recruitment to CXCR7 by
TC14012 is much higher than that of the previously reported CXCR4 antagonist
AMD3100 and differs only by one log from that of the natural
ligand CXCL12 (EC(50) 350 nM for
TC14012, as compared with 30 nM for CXCL12 and 140 μM for
AMD3100). Moreover, like CXCL12,
TC14012 leads to Erk 1/2 activation in U373
glioma cells that express only CXCR7, but not CXCR4. Given that with
TC14012 and
AMD3100 two structurally unrelated CXCR4 antagonists turn out to be agonists on CXCR7, this likely reflects differences in the activation mechanism of the
arrestin pathway by both receptors. To identify the receptor domain responsible for these opposed effects, we investigated CXCR4 and CXCR7 C terminus-swapping chimeras. Using quantitative bioluminescence resonance energy transfer, we find that the CXCR7 receptor core formed by the seven-transmembrane domains and the connecting loops determines the agonistic activity of both
TC14012 and
AMD3100. Moreover, we find that the CXCR7 chimera bearing the CXCR4 C-terminal constitutively associates with
arrestin in the absence of
ligands. Our data suggest that the CXCR4 and CXCR7 cores share
ligand-binding surfaces for the binding of the synthetic
ligands, indicating that CXCR4 inhibitors should be tested also on CXCR7.