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.

Insight into SUCNR1 (GPR91) structure and function

“…Several authors repeatedly confirmed G i activation by demonstrating a decrease of cAMP levels upon succinate binding to SUCNR1 (Fig. 3), in both heterologous and native systems (Gilissen et al, 2015;Gnana-Prakasam et al, 2011 ;Hakak et al, 2009;Hogberg et al, 2011 ;Sundström et al, 2013). However, the view of SUCNR1 being coupled to G q has been challenged and it was proposed by several authors that the observed [Ca 2+ ] i mobilization was a consequence of PLC-β activation by the βγ dimer (Fig.…”

“…3). Some results indicate that ERK activation is G i -dependent and should probably be mediated through the dimer βγ (Gilissen et al, 2015;Hakak et al, 2009). SUCNR1 is internalized into vesicular structures upon succinate exposure in HEK293 cells (He et al, 2004).…”

“…SUCNR1 is expressed in megakaryocytes at both protein and mRNA levels (Hakak et al, 2009;Macaulay et al, 2007). SUCNR1 is expressed in hematopoietic progenitor cells (HPC) of the bone marrow.…”

“…The proliferative effect seems to be mediated through G i pathway that leads to the activation of ERK1/2 and inositol phosphate (IP) increase. These pathways are relevant for HPC proliferation, differentiation, and survival (Hakak et al, 2009). SUCNR1 also stimulates blood cell development by increasing the levels of hemoglobin, platelets, and neutrophils in a mouse model of chemotherapy-induced myelosuppression (Hakak et al, 2009).…”

Hemodynamic effects of succinate-containing dialyzing solution

“…Отчасти этот эффект может быть объяснен гемоконцентрацией вследствие уменьшения общей гидратации больных. Имеются, од-нако, данные о том, что сукцинат способен стимулиро-вать пролиферацию эритроидного ростка: уменьшение катаболизма HIF, обусловленное сукцинатом, активиру-ет экспрессию генов не только VEGF, но и эритропоэти-на [41].…”