A New Spin on an Old Cycle

Science's STKE  25 May 2004:
Vol. 2004, Issue 234, pp. tw184
DOI: 10.1126/stke.2342004TW184

During a search for natural ligands of orphan GPCRs [heterotrimeric guanine-nucleotide-binding protein (G protein)-coupled receptors], He et al. uncovered an unexpected link between cell metabolism and cell signaling with intriguing implications for the pathogenesis of metabolic disease. The citric acid cycle, in which fuel molecules are broken down to yield energy and CO2, takes place in the mitochondria. However, citric acid cycle intermediates are found in the blood at micromolar concentrations, where their levels are controlled by absorption and extrusion by the kidneys, as well as by respiration and metabolism. He et al. purified a compound that activated cells expressing the orphan GPCR GPR91, which they identified as the citric acid cycle intermediate succinate. When applied to 293 cells stably expressing human GPR91, succinate elicited increases in intracellular calcium and inositol phosphate, activated extracellular signal-regulated kinase, and inhibited adenosine 3′,5′-monophosphate production. These data, together with sensitivity to pertussis toxin, indicated that succinate stimulation of GPR91 activated at least two G protein-mediated signaling pathways (Gi or Go and Gq). A second citric acid cycle intermediate, α-ketoglutarate, activated a Gq pathway through the closely related orphan GPCR GPR99. The mRNAs for GPR91 and GPR99 were predominantly localized to the kidney, and intravenous injection of succinate elicited increases in plasma renin activity and mean arterial blood pressure in rats; in mice, the effect of succinate on blood pressure depended on GPR91 expression. Thus, succinate and α-ketoglutarate serve as ligands for GPR91 and GPR99, respectively, and succinate may thereby link cell metabolism and blood pressure regulation.

W. He, F. J.-P. Miao, D. C.-H. Lin, R. T. Schwandner, Z. Wang, J. Gao, J.-L. Chen, H. Tian, L. Ling, Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188-193 (2004). [Online Journal]