Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.
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.
He
Weihai
W
Tularik Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
Miao
Frederick J-P
FJ
Lin
Daniel C-H
DC
Schwandner
Ralf T
RT
Wang
Zhulun
Z
Gao
Jinhai
J
Chen
Jin-Long
JL
Tian
Hui
H
Ling
Lei
L
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
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