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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.
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“Maintaining the anti-inflammatory (reparative) M2 phenotype of macrophages and microglia is crucial for PGC-1α induction in penumbral neurons since the M2 phenotype is the main source of neurotrophins, which are positive modulators of PGC-1α [17,90].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [90]
In the citing paper
“He and colleagues made an important discovery when they found that the Krebs cycle-derived metabolites, succinate and α-KG, acted as ligands for the orphan G-protein coupled receptors GPR91 (now known as SUCNR1) and GPR99 (now known as OXRG1), respectively3.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [3]
In the citing paper
“The authors demonstrated that succinate acted as an important hypertensive agent, modulating the renin-angiotensin system via SUCNR1 signalling, independent of its role in bioenergetics3.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [3]
In the citing paper
“SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine3, and on dendritic cells (DCs) 4 and ligand binding induces Gi and Gq signalling cascades3.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [3]
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Metadata
- Authors
- He, W., Miao, F. J.-P., Lin, D. C.-H., Schwandner, R. T., Wang, Z., Gao, J., Chen, J.-L., Tian, H., & Ling, L.
- Affiliations
- University of Regensburg (DE)
- Corresponding author
- Ling, Lei
- Venue
- Nature
- Published
- 2004-05
- Volume
- 429
- Issue
- 6988
- Pages
- 188-193
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2085901707
- Cited by
- 909
- References
- 31
- Citations by year
- 2026: 54 · 2025: 52 · 2024: 51 · 2023: 47 · 2022: 57 · 2021: 62 · 2020: 63 · 2019: 53 · 2018: 53 · 2017: 44 · 2016: 48 · 2015: 21 · 2014: 42 · 2013: 34 · 2012: 27
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- GPR91, orphan G protein-coupled receptor, succinic acid, alpha-ketoglutarate, citric acid cycle intermediates, receptor ligands, blood pressure regulation, renovascular hypertension, renin-angiotensin system, G protein-coupled receptor signaling
- MeSH terms
- Animals, Antihypertensive Agents, Captopril, Cattle, Cell Line, Citric Acid Cycle, Cricetinae, Humans, Hypertension, Ketoglutaric Acids, Kidney, Ligands, Models, Molecular, Protein Conformation, Renin-Angiotensin System, Rhodopsin, RNA, Messenger, Swine, Rats, Sprague-Dawley, Succinic Acid, Pertussis Toxin, Receptors, G-Protein-Coupled, Mice, Rats
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