Grk2 is an essential regulator of CXCR7 signalling in astrocytes.

We previously demonstrated that in astrocytes, SDF-1/CXCL12 exclusively signals through CXCR7 despite the additional presence of the alternate SDF-1/CXCL12 receptor, CXCR4. In addition, we provided evidence that astrocytic CXCR7-signalling involves a G protein-dependent mechanism. This is insofar remarkable as in all other cell types studied to date, CXCR7 either acts as a scavenger chemokine receptor, a modulator of CXCR4, or a non-classical chemokine receptor, signalling through ß-arrestin. To begin to unravel the molecular framework impinging the selective function of CXCR7 on a given cell type, we have now analysed the role of G protein-coupled receptor kinases (Grks) in astrocytic CXCR7 signalling. We demonstrate that Grk2 mediates signalling of SDF-1/CXCL12-bound CXCR7 as suggested by the finding that SDF-1/CXCL12-induced activation of Erk1/2 and Akt is abrogated following RNAi-mediated inhibition of Grk2, but not of Grk3, Grk5, or Grk6. We further unravel that Grk2 additionally controls signalling of SDF-1/CXCL12-bound CXCR7 in astrocytes by mediating internalization and subsequent silencing of CXCR7. Finally, we demonstrate that Grk2 is likewise expressed by microglial cells and Schwann cells, cell types in which CXCR7 does not act as a classical chemokine receptor. In conclusion, our findings establish that Grk2 tightly controls CXCR7 signalling in astrocytes, but does not imprint the cell type-specific function of this chemokine receptor.