title: Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.
abstract: 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 alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-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.
authors.affiliation: Tularik Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
authors.forename: Weihai
authors.initials: W
authors.lastname: He
authors.forename: Frederick J-P
authors.initials: FJ
authors.lastname: Miao
authors.forename: Daniel C-H
authors.initials: DC
authors.lastname: Lin
authors.forename: Ralf T
authors.initials: RT
authors.lastname: Schwandner
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jinhai
authors.initials: J
authors.lastname: Gao
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Lei
authors.initials: L
authors.lastname: Ling
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002952:Citric Acid Cycle / Q000502:physiology*; D006224:Cricetinae; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D007656:Ketoglutaric Acids / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D037342:Pertussis Toxin / Q000494:pharmacology; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012243:Rhodopsin / Q000737:chemistry; D019802:Succinic Acid / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine
chemical_list: D000959:Antihypertensive Agents; D007656:Ketoglutaric Acids; D008024:Ligands; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin; D002216:Captopril; D019802:Succinic Acid; D037342:Pertussis Toxin