CCL5 activates a orphan G-protein coupled receptor 75 in human neuroblastoma SH-SY5Y cell line. 15-19 NOVEMBER, WASHINGTON DC

The chemokine CCL5 inhibits entry of M-tropic HIV strains into macrophages/microglia by affecting the binding of the envelop protein gp120 to the co-receptor CCR5. Interestingly, CCL5 also prevents neuronal cell death mediated by the T-tropic gp120 and the viral protein Tat, which have no affinity for CCR5. Thus, CCL5 could be used to reduce HIV-associated neurocognitive disorder (HAND). Nevertheless, the mechanism of action of CCL5 remains to be fully characterized. Recent studies have shown that CCL5 activates a G-protein coupled receptor 75 (GPR75) which encodes for a 540 amino-acid orphan receptor of the Gq α family. In the present study, we examined the interaction of CCL5 and GPR75 in neuroblastoma SH-SY5Y cells that do not express other receptors for CCL5, such as CCR5, CCR3, and CCR1. CCL5 then promoted GPR75 internalization within few minutes. In addition, CCL5 elicited a significant dose-dependent increase in pro-survival pathways, such as the phosphatidylinositol 3-kinase (PI3K) and the extracellular signal-regulated kinases (ERK1/2). Akt and ERK1/2 phosphorylation were blocked by the specific pathway inhibitors, Wortmannin and U73 122, respectively, but not by pertuxin toxin, suggesting that CCL5 activate a Gq-coupled receptor. In conclusion, we hypothesize that CCL5-GPR75 signaling could further activate a neuroprotective mechanism that could explain the multiple pro-survival roles of CCL5 in reducing gp120 and Tat cell death