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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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“The intrarenal RAAS is activated early in diabetes yet the exact mechanism is unknown. The discovery of GPR91, a G-protein-coupled receptor that is activated by succinate [”
BackgroundMetabolic Modulation in Macrophage Effector Function
Diskin, C., & Pålsson‐McDermott, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00270 · Cited by 310
“GPR91, which has since been renamed the succinate receptor (SUCNR1), was found to be expressed in a wide variety of tissues (86).”
BackgroundLewis, G. D., Wei, R., Liu, E. H., Yang, E., Shi, X., Martinovic, M. F., Farrell, L. A., Asnani, A. H., Cyrille, M., Ramanathan, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35111 · Cited by 282
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“Succinate activates Sucnr1 at millimolar or submillimolar ranges (21), and the type 2 immune responses were strongly evident when 100 mM succinate was ingested but barely detectable when 10 or 1 mM succinate was ingested (SI Appendix, Fig.”
BackgroundMethodpH-gated succinate secretion regulates muscle remodeling in response to exercise
Reddy, A., Bozi, L. H. M., Yaghi, O. K., Mills, E. L., Xiao, H., Nicholson, H. E., Paschini, M., Paulo, J. A., Garrity, R., Laznik-Bogoslavski, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.039 · Cited by 279
“The half-maximal response (EC50) for succinate-induced activation of SUCNR1 is reported to be in the range of 28–56 mM, and 99% responses are achieved at 200 mMor higher (He et al., 2004).”
BackgroundG protein-coupled receptors for energy metabolites as new therapeutic targets
Blad, C. C., Tang, C., & Offermanns, S. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3777 · Cited by 277
The Metabolic Basis of Pulmonary Arterial Hypertension
Sutendra, G., & Michelakis, E. D. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.004 · Cited by 271
Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications
Sas, K. M., Kayampilly, P., Byun, J., Nair, V., Hinder, L. M., Hur, J., Zhang, H., Lin, C., Qi, N. R., Michailidis, G., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.86976 · Cited by 268
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Pathophysiology of the Diabetic Kidney
Vallon, V., & Komers, R. (2011) · Comprehensive physiology · doi:10.1002/cphy.c100049 · Cited by 291
The Pharmacology and Function of Receptors for Short-Chain Fatty Acids
Bolognini, D., Tobin, A. B., Milligan, G., & Hodge, D. (2016) · Molecular Pharmacology · doi:10.1124/mol.115.102301 · Cited by 267
“Previous studies had shown that positively charged amino acids within the TM regions are essential for the binding and function of other GPCRs whose ligands contain a carboxylic acid group (Stitham et al., 2003; He et al., 2004; Tunaru et al., 2005; Sabirsh et al., 2006).”
BackgroundBezençon, C., Fürholz, A., Raymond, F., Mansourian, R., Métairon, S., le Coutre, J., & Damak, S. (2008) · The Journal of Comparative Neurology · doi:10.1002/cne.21768 · Cited by 251
“Succinate was recently shown to increase blood pressure in mice through the reninangiotensin system, and this effect is eliminated in succinate receptor knockout mice (He et al., 2004).”
BackgroundIntracellular and Intercellular Aspects of Macrophage Immunometabolism in Atherosclerosis
Tabas, I. A., & Bornfeldt, K. (2020) · Circulation Research · doi:10.1161/circresaha.119.315939 · Cited by 253
GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors
Ahmed, K., Tunaru, S., & Offermanns, S. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.09.001 · Cited by 260
The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications
Xiao, D., Zeng, L., Kang, Y., Kong, X., Wu, G., & Yin, Y. (2016) · Amino Acids · doi:10.1007/s00726-016-2254-8 · Cited by 246
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The Immunomodulatory Potential of the Metabolite Itaconate
Hooftman, A., & O'Neill, L. A. J. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.05.007 · Cited by 236
Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13)
Bahn, A., Hagos, Y., Reuter, S., Balen, D., Brzica, H., Krick, W., Burckhardt, B. C., Sabolić, I., & Burckhardt, G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800737200 · Cited by 227
Application of Metabolomics to Cardiovascular Biomarker and Pathway Discovery
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Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition
Shaul, Y. D., Freinkman, E., Comb, W. C., Cantor, J. R., Tam, W. L., Thiru, P., Kim, D., Kanarek, N., Pacold, M. E., Chen, W. W., et al. (2014) · Cell · doi:10.1016/j.cell.2014.07.032 · Cited by 223
“…similar to serine in the case of the glycolytic enzyme pyruvate kinase M2 (PKM) (Chaneton et al., 2012), or as receptor ligands, like the citric acid cycle intermediates succinate and α-ketoglutarate in the case of the G-protein coupled receptors GPR99 and GPR91, respectively (He et al., 2004).”
BackgroundA chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors
Surgand, J.-S., Rodrigo, J., Kellenberger, E., & Rognan, D. (2005) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20768 · Cited by 220
“to be anchoring points for succininic acid and -ketoglutaric acid to GPR80/GPR91.(185) The modeled TM cavity of”
BackgroundOncometabolites in renal cancer
Yong, C., Stewart, G. D., & Frezza, C. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0210-z · Cited by 216
Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0406-x · Cited by 221
“The GPR99 receptor has so far been found in kidney, placenta, testis, smooth muscles, trachea, and mast cells (He et al. 2004; Wittenberger et al. 2002), however, its”
BackgroundUpdate on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7
Bäck, M., Powell, W. S., Dahlén, S., Drazen, J. M., Evans, J. F., Serhan, C. N., Shimizu, T., Yokomizo, T., & Rovati, G. E. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12665 · Cited by 217
“, 2002), was initially recognized as an oxoglutarate receptor based on its binding of and activation by 2-oxoglutarate (α-ketoglutarate) with potency in the high micromolar range via a Gq-mediated pathway (He et al., 2004).”
BackgroundImmunometabolic circuits in trained immunity
Arts, R. J. W., Joosten, L. A. B., & Netea, M. G. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.09.002 · Cited by 228
Carbon/Nitrogen Metabolic Balance: Lessons from Cyanobacteria
Zhang, C., Zhou, C., Burnap, R. L., & Peng, L. (2018) · Trends in Plant Science · doi:10.1016/j.tplants.2018.09.008 · Cited by 206
Organic Anion Transporter Family: Current Knowledge
Anzai, N., Kanai, Y., & Endou, H. (2006) · Journal of Pharmacological Sciences · doi:10.1254/jphs.crj06006x · Cited by 209
Wellendorph, P., Hansen, K. B., Balsgaard, A., Greenwood, J. R., Egebjerg, J., & Bräuner‐Osborne, H. (2004) · Molecular Pharmacology · doi:10.1124/mol.104.007559 · Cited by 207
“By analogy, a recently published study found GPCRs to respond to specific intermediates of the citric acid cycle (He et al., 2004), implying that such metabolites, well known for their biochemistry, may also function as signaling molecules.”
BackgroundMetabolite sensing and signaling in cell metabolism
Wang, Y.-P., & Lei, Q. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0024-7 · Cited by 208
“Functional experiments further demonstrated that GPR91 signaled succinate to downstream signaling pathways and mediated hypertensive effects through activating the reninangiotensin system.(36)”
BackgroundZhang, Y., Chen, R., Zhang, D., Qi, S., & Liu, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114295 · Cited by 224
I want a new drug: G-protein-coupled receptors in drug development
Schlyer, S., & Horuk, R. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.04.008 · Cited by 204
Mitochondria as Cellular and Organismal Signaling Hubs
Shen, K., Pender, C. L., Bar‐Ziv, R., Zhang, H., Wickham, K., Willey, E., Durieux, J., Ahmad, Q., & Dillin, A. G. (2022) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120420-015303 · Cited by 214
Cytokine-like Roles for Metabolites in Immunity
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An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans
Amisten, S., Salehi, A. A., Rorsman, P., Jones, P. M., & Persaud, S. J. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.05.004 · Cited by 205
Intermediates of Metabolism: From Bystanders to Signalling Molecules
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“In mouse it is expressed mainly in the kidney, liver, spleen, and small intestine [5].”
BackgroundG Protein–Coupled Receptor Deorphanizations
Civelli, O., Reinscheid, R. K., Zhang, Y., Wang, Z., Fredriksson, R., & Schiöth, H. B. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134548 · Cited by 199
“Other surprises as unexpected transmitters are succinate and α-ketoglutarate, which activate the orphan GPCRs GPR91 and GPR99, respectively, with affinities in the 25–70-μM range (70).”
BackgroundSelf-citationSUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes
van Diepen, J. A., Robben, J. H., Hooiveld, G. J., Carmone, C., Alsady, M., Boutens, L., Bekkenkamp-Grovenstein, M., Hijmans, A., Engelke, U. F. H., Wevers, R. A., et al. (2017) · Diabetologia · doi:10.1007/s00125-017-4261-z · Cited by 187
“Importantly, with the identification of G-coupled receptor 91 (GPR91), also known as succinate receptor 1 (SUCNR1), which is present on the plasma membrane of various cell types, it became clear that succinate may have an important signalling function, providing feedback between local tissue metabolism, mitochondrial…”
BackgroundMethod
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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