title: The role of the GPR91 ligand succinate in hematopoiesis.
abstract: 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.
authors.affiliation: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yhakak@arenapharm.com
authors.forename: Yaron
authors.initials: Y
authors.lastname: Hakak
authors.forename: Karin
authors.initials: K
authors.lastname: Lehmann-Bruinsma
authors.forename: Shirley
authors.initials: S
authors.lastname: Phillips
authors.forename: Thuy
authors.initials: T
authors.lastname: Le
authors.forename: Chen
authors.initials: C
authors.lastname: Liaw
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Connolly
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
mesh_terms: 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*
chemical_list: D018952:Antigens, CD34; D008024:Ligands; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D019802:Succinic Acid