The presumed atypical chemokine receptor CXCR7 signals through G(i/o) proteins in primary rodent astrocytes and human glioma cells

Glia. 2012 Mar;60(3):372-81. doi: 10.1002/glia.22271. Epub 2011 Nov 14.


SDF-1/CXCL12 binds to the chemokine receptors, CXCR4 and CXCR7, and controls cell proliferation and migration during development, tumorigenesis, and inflammatory processes. It is currently assumed that CXCR7 would represent an atypical or scavenger chemokine receptor which modulates the function of CXCR4. Contrasting this view, we demonstrated recently that CXCR7 actively mediates SDF-1 signaling in primary astrocytes. Here, we provide evidence that CXCR7 affects astrocytic cell signaling and function through pertussis toxin-sensitive G(i/o) proteins. SDF-1-dependent activation of G(i/o) proteins and subsequent increases in intracellular Ca(2+) concentration persisted in primary rodent astrocytes with depleted expression of CXCR4, but were abolished in astrocytes with depleted expression of CXCR7. Moreover, CXCR7-mediated effects of SDF-1 on Erk and Akt signaling as well as on astrocytic proliferation and migration were all sensitive to pertussis toxin. Likewise, pertussis toxin abolished SDF-1-induced activation of Erk and Akt in CXCR7-only expressing human glioma cell lines. Finally, consistent with a ligand-biased function of CXCR7 in astrocytes, the alternate CXCR7 ligand, I-TAC/CXCL11, activated Erk and Akt through β-arrestin. The demonstration that SDF-1-bound CXCR7 activates G(i/o) proteins in astrocytes could help to explain some discrepancies previously observed for the function of CXCR4 and CXCR7 in other cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Arrestins / metabolism
  • Astrocytoma / pathology
  • Calcium / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Chemokine CXCL12 / metabolism
  • Chemotaxis / drug effects
  • Chemotaxis / genetics
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
  • Humans
  • Mice
  • Mice, Knockout
  • Neuroglia / drug effects
  • Neuroglia / metabolism*
  • RNA Interference / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism*
  • Receptors, CXCR4 / deficiency
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sulfur Isotopes / pharmacokinetics
  • beta-Arrestins


  • ACKR3 protein, human
  • Arrestins
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Enzyme Inhibitors
  • Receptors, CXCR
  • Receptors, CXCR4
  • Sulfur Isotopes
  • beta-Arrestins
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Calcium