A New Spin on an Old Cycle

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Science  04 Jun 2004:
Vol. 304, Issue 5676, pp. 1417
DOI: 10.1126/science.304.5676.1417c

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. isolated a compound that activated cells expressing the orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) GPR91, which was identified as the citric acid cycle intermediate succinate. When applied to mammalian 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 an observed sensitivity to pertussis toxin, indicate that succinate stimulation of GPR91 activates 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 are predominantly localized in 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. — EMA

Nature 429, 188 (2004).

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