Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes

CXCR4 is the Gi protein-linked seven-transmembrane receptor for the alpha c hemokine stromal cell-derived factor 1 (SDF-1), a chemoattractant for lymph ocytes, This receptor is highly conserved between human and rodent. CXCR4 i s also a coreceptor for entry of human immunodeficiency virus (HIV) in T ce lls and is expressed in the CNS. To investigate how these CXCR4 ligands inf luence CNS development and/or function, we have examined the expression and signalling of this chemokine receptor in rat neurons and astrocytes in vit ro. CXCR4 transcripts and protein are synthesized by both cell types and in E15 brain neuronal progenitors. In these progenitors, SDF-1, but not gp120 (the HIV glycoprotein), induced activation of extracellular signal regulat ed kinases (ERKs) 1/2 and a dose-dependent chemotactic response. This chemo taxis was inhibited by Pertussis toxin, which uncouples Gi proteins and the bicyclam AMD3100, a highly selective CXCR4 antagonist, as well as by an in hibitor of the MAP kinase pathway. In differentiated neurons, both SDF-1 an d the glycoprotein of HIV, gp120, triggered activation of ERKs with similar kinetics. These effects were significantly inhibited by Pertussis toxin an d the CXCR4 antagonist. Rat astrocytes also responded to SDF-1 signalling b y phosphorylation of ERKs but, in contrast to cortical neurons, no kinase a ctivation was induced by gp120, Thus neurons and astrocytes can respond dif ferently to signalling by SDF-1 and/or gp120. As SDF-1 triggers directed mi gration of neuronal progenitors, this alpha chemokine may play a role in co rtex development. In differentiated neurons, both natural and viral ligands of CXCR4 activate ERKs and may therefore influence neuronal function.