The chemokine CCL5 affects the binding of the envelop protein gp120 to the co-receptor CCR5. CCL5 also prevents neuronal cell death mediated by the X4 gp120 and Tat, which have no affinity for CCR5. The mechanism of action of this chemokine remains to be fully characterized. Recent studies and preliminary data have shown that CCL5 activates a GPR75 which belongs to the Gqα family. This receptor is more abundant in the brain than in the immune organs. Moreover, CCL5 activates various pro-survival signaling molecules, including inositol triphosphate, phosphatidylinositol 3-kinase and its downstream targets, protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), in SH-SY5Y human neuroblastoma cells. These cells do not express CCR5, CCR3 and CCR1, receptors known to bind to CCL5. Moreover, CCL4, CCL7 and CCL3, other chemokines that bind to CCR5, CCR3 and CCR1, failed to activate these signaling molecules in SH-SY5Y cells. Akt and ERK1/2 phosphorylation were blocked by the Wortmannin and U73122, inhibitors of Akt and ERK1/2, respectively. At the same time these responses were insensitive to pertussis toxin, a Gi inhibitor, suggesting that CCL5 activates a GPCR coupled to Gq proteins. Therefore, GPR75 could explain the neuroprotective activity of CCL5 against gp120 and Tat. The discovery and characterization of compounds that prevent or limit the neurodegeneration that follows HIV infection of the brain is a great challenge for HIV research. Thus, the results provide new mechanistic insight which can be instrumental in addressing this challenge. Supported by NS 079172, NS 074916, DA 032282
CCL5 activates a orphan G-protein coupled receptor 75 Neuroprotective effect of CCL5 via the G-protein coupled receptor 75 (GPR75) activation. 20th Meeting of Society of NeuroImmune Pharmacology (SNIP). 26-29 March, 2014 New Orleans, U.S.A.
DEDONI, SIMONA;
2014-01-01
Abstract
The chemokine CCL5 affects the binding of the envelop protein gp120 to the co-receptor CCR5. CCL5 also prevents neuronal cell death mediated by the X4 gp120 and Tat, which have no affinity for CCR5. The mechanism of action of this chemokine remains to be fully characterized. Recent studies and preliminary data have shown that CCL5 activates a GPR75 which belongs to the Gqα family. This receptor is more abundant in the brain than in the immune organs. Moreover, CCL5 activates various pro-survival signaling molecules, including inositol triphosphate, phosphatidylinositol 3-kinase and its downstream targets, protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), in SH-SY5Y human neuroblastoma cells. These cells do not express CCR5, CCR3 and CCR1, receptors known to bind to CCL5. Moreover, CCL4, CCL7 and CCL3, other chemokines that bind to CCR5, CCR3 and CCR1, failed to activate these signaling molecules in SH-SY5Y cells. Akt and ERK1/2 phosphorylation were blocked by the Wortmannin and U73122, inhibitors of Akt and ERK1/2, respectively. At the same time these responses were insensitive to pertussis toxin, a Gi inhibitor, suggesting that CCL5 activates a GPCR coupled to Gq proteins. Therefore, GPR75 could explain the neuroprotective activity of CCL5 against gp120 and Tat. The discovery and characterization of compounds that prevent or limit the neurodegeneration that follows HIV infection of the brain is a great challenge for HIV research. Thus, the results provide new mechanistic insight which can be instrumental in addressing this challenge. Supported by NS 079172, NS 074916, DA 032282
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