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RANTES stimulates Ca 2+ mobilization and inositol trisphosphate (IP 3 ) formation in cells transfected with G protein‐coupled receptor 75
Author(s) -
Ignatov A,
Robert J,
GregoryEvans C,
Schaller H C
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706909
Subject(s) - wortmannin , microbiology and biotechnology , phospholipase c , g protein coupled receptor , transfection , signal transduction , mapk/erk pathway , protein kinase b , phosphatidylinositol , gq alpha subunit , chemistry , g protein , biology , cell culture , genetics
Background and purpose: RANTES is an inflammatory chemokine with a critical role in T‐lymphocyte activation and proliferation. Its effects are mediated through G protein‐coupled heptahelical receptors (GPCRs). We show for the first time that RANTES activates the orphan G protein‐coupled receptor 75 (GPR75). Experimental approach: To identify a ligand for GPR75 we have used three different and independent methods, namely luciferase assay, bioluminescence assay and IP 3 accumulation assay. Key results: Treatment of cells expressing GPR75 with subnanomolar concentrations of RANTES led to stimulation of the luciferase activity in a reporter‐gene assay, an increase in inositol trisphosphate, and intracellular Ca 2+ . The latter effect was blocked by the phospholipase‐C inhibitor (PLC) U73122 indicating that Gq proteins mediate GPR75 signaling. RANTES enhanced the phosphorylation of AKT and mitogen‐activated protein kinase (MAPK) in GPR75‐transfected cells and this effect was blocked by the PLC inhibitor U73122 and the phosphatidylinositol 3‐kinase (PI3K) inhibitor, wortmannin. The hippocampal cell line HT22, which expresses GPR75 endogenously, but not the other known RANTES receptors, was used to study the effects of RANTES and GPR75 on neuronal survival. Treatment of HT22 cells with RANTES significantly reduced the neurotoxicity of amyloid‐β peptides, by activating PLC and PI3K. Conclusions and implications: This demonstrate clearly and undoubtedly the ability of RANTES to act on GPR75. Defects in the RANTES/GPR75‐signaling pathway may contribute to neuroinflammatory and neurodegenerative processes as observed in Alzheimer's disease. British Journal of Pharmacology (2006) 149 , 490–497. doi: 10.1038/sj.bjp.0706909