The role of the GPR91 ligand succinate in hematopoiesis.
Regulation of cellular metabolism by the citric acid cycle occurs in the mitochondria. However, the citric acid cycle intermediate succinate was shown recently to be a ligand for the G-protein-coupled receptor GPR91. Here, we describe a role for succinate and its receptor in the stimulation of hematopoietic progenitor cell (HPC) growth. GPR91 mRNA and protein expression were detected in human bone marrow CD34+ progenitor cells, as well as in erythroid and megakaryocyte cultures and the erythroleukemic cell line TF-1. Treatment of these cell cultures with succinate resulted in increased proliferation rates. The proliferation response of TF-1 cells was pertussis toxin (PTX)-sensitive, suggesting a role for Gi signaling. Proliferation was also blocked when TF-1 cells were transfected with small interfering RNA specific for GPR91. Succinate stimulated activation of the Erk MAPK pathway and inositol phosphate accumulation in a PTX-sensitive manner. Pretreatment of TF-1 cells with the Erk1/2 kinase (MEK) inhibitor PD98059 blocked the proliferation response. Succinate treatment additionally protected TF-1 cells from cell death induced by serum deprivation. Finally, in vivo administration of succinate was found to elevate the levels of hemoglobin, platelets, and neutrophils in a mouse model of chemotherapy-induced myelosuppression. These results suggest that succinate-GPR91 signaling is capable of promoting HPC development.
Hakak
Yaron
Y
Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yhakak@arenapharm.com
Lehmann-Bruinsma
Karin
K
Phillips
Shirley
S
Le
Thuy
T
Liaw
Chen
C
Connolly
Daniel T
DT
Behan
Dominic P
DP
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D019802:Succinic Acid / Q000494:pharmacology*
D018952:Antigens, CD34; D008024:Ligands; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D019802:Succinic Acid