Document Detail


Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.
MedLine Citation:
PMID:  15141213     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Weihai He; Frederick J-P Miao; Daniel C-H Lin; Ralf T Schwandner; Zhulun Wang; Jinhai Gao; Jin-Long Chen; Hui Tian; Lei Ling
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Nature     Volume:  429     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-13     Completed Date:  2004-06-02     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  188-93     Citation Subset:  IM    
Affiliation:
Tularik Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antihypertensive Agents / pharmacology
Captopril / pharmacology
Cattle
Cell Line
Citric Acid Cycle / physiology*
Cricetinae
Humans
Hypertension / physiopathology
Ketoglutaric Acids / metabolism,  pharmacology
Kidney / chemistry
Ligands
Mice
Models, Molecular
Pertussis Toxin / pharmacology
Protein Conformation
RNA, Messenger / genetics,  metabolism
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / chemistry,  deficiency,  genetics,  metabolism*
Renin-Angiotensin System / physiology
Rhodopsin / chemistry
Succinic Acid / metabolism*,  pharmacology
Swine
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Ketoglutaric Acids; 0/Ligands; 0/RNA, Messenger; 0/Receptors, G-Protein-Coupled; 110-15-6/Succinic Acid; 328-50-7/alpha-ketoglutaric acid; 62571-86-2/Captopril; 9009-81-8/Rhodopsin; EC 2.4.2.31/Pertussis Toxin
Comments/Corrections
Comment In:
Nature. 2004 May 13;429(6988):143-5   [PMID:  15141197 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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