Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

• Published in: Nature Vol. 429; no. 6988; pp. 188 - 193
• Main Authors: Ling, Lei, He, Weihai, Miao, Frederick J.-P, Lin, Daniel C.-H, Schwandner, Ralf T, Wang, Zhulun, Gao, Jinhai, Chen, Jin-Long, Tian, Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 13.05.2004; Nature Publishing Group
• Subjects: Acids; Animals; Antihypertensive Agents - pharmacology; Biological and medical sciences; Captopril - pharmacology; Cattle; Cell Line; Citric Acid Cycle - physiology; Cricetinae; Fundamental and applied biological sciences. Psychology; Hemodynamics. Rheology; Humans; Hypertension; Hypertension - physiopathology; Ketoglutaric Acids - metabolism; Ketoglutaric Acids - pharmacology; Kidney - chemistry; Ligands; Metabolism; Mice; Models, Molecular; Pertussis Toxin - pharmacology; Protein Conformation; Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Renin-Angiotensin System - physiology; Rhodopsin - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Succinic Acid - metabolism; Succinic Acid - pharmacology; Swine; Vertebrates: cardiovascular system; Hypertension; Metabolic intermediate; Binding protein; GTP; Ligand; Succinic acid; Cardiovascular disease; Metabolism; Citric acid; Orphan receptor; G protein
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02488

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to α-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and α-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.