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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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“Although chiefly found in the mitochondria, succinate is also found in the plasma in the mm range [3].”
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“In mice, GPR99 was shown to increase chloride and bicarbonate exchange and promote NaCl reabsorption when activated by αKG 136,142 .”
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“GPR91 was then renamed SUCNR1, succinate being is its exclusive endogenous ligand described up to now, with a EC50 in the range of 28–56 μM (depending on the read-out used to assess [Ca]i) [82].”
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“It has been described that restricted organ blood supply (local ischemia) induced the accumulation of succinate in different hypertensive animal models resulting in a subsequent renin release (38).”
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Patananan, A. N., Sercel, A. J., & Teitell, M. A. (2017) · Current Opinion in Physiology · doi:10.1016/j.cophys.2017.11.006 · Cited by 11
“For example, succinate and aKG can bind to GPCR91 and GPCR99, respectively, to regulate cellular functions and tissue physiology [54,55].”
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Hoque, M., Ali, S., & Hoda, M. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2018.07.091 · Cited by 9
Yak OXGR1 promotes fibroblast proliferation via the PI3K/AKT pathways
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“OXGR1 (entitled GPR80/GPR99/, P2RY15/P2Y15) was firstly identified as a citric acid cycle intermediates in succinate and α‐ketoglutarate (αKG) plasma membrane‐ bound receptors.(6) Recently, OXGR1 was identified as another ligand of leukotriene E4 (LTE4) and demonstrated an influence in vascular permeability and edema…”
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Lantz, C. W., Becker, A., & Thorp, E. B. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.07.003 · Cited by 10
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Increased succinate receptor GPR91 involved in the pathogenesis of Mooren’s ulcer
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“Succinate receptor 1, abbreviated as SUCNR1, is a G protein-coupled receptor (GPR91) associated with the P2Y purinergic receptor family, activated by succinate, an inter - mediate metabolite in the Krebs cycle [ 70].”
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“Further, the succinate receptor (SUCNR1/GPR91), expressed in several tissues [130], is up-regulated in inflammatory macrophages [131].”
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“102,103 Meanwhile, in the TCA cycle, succinate is derived from the conversion of α-ketoglutarate (α-KG), and these two metabolites are closely linked in cellular metabolic pathways.”
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“Succinate anions act as a metabolic intermediate and a signaling molecule [27].”
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“It is expressed in various types of cells of the body and serves as a system for detecting extreme states (local stress), such as ischemia, hypoxia, tissue damage, and inflammation [1].”
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“It is also demonstrated that an increase in extracellular succinate concentrations through the interaction of GPR91-receptors associated with G-proteins leads to the activation of intracellular metabolism [26].”
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“…according to the specific protocol using n = 6–8 animals per group: sham-operated (sham), 2K1C surgery (2K1C), 2K1C surgery plus minipump implantation with Montelukast (577953-88-9 Merk, Darmstadt, Germany) (2K1C + ML), Oxgr1 − / − sham-operated (KO), or Oxgr1 − / − with 2K1C surgery (2K1C KO).”
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“GPR91 (also known as succinate receptor 1, SUCNR) is able to be activated by succinate to stimulate the release of intracellular calcium ions, inhibiting cAMP production [41].”
Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity
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Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis
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“Extracellular succinate exerts its effect on several cell types through the succinate receptor (SUCNR1), also known as the G-protein coupled receptor 91 (GPR91) (22).”
Metabolic Effects of Succinate Dehydrogenase Loss in Cancer
Chatoff, A. G., Kantner, D. S., Snyder, N. W., & Rink, L. A. (2025) · Journal of Cellular Physiology · doi:10.1002/jcp.70066 · Cited by 10
“Succinate has distinct signaling functions as it has both a specific receptor, the GPCR succinate receptor 1 (SUCNR1), and is the product of α ‐ ketoglutarate ( α ‐ KG) dependent dioxygenases ( α KGDHs) (He et al. 2004; E. H. Smith et al. 2007).”
Silybin inhibits succinate production and secretion in hepatocytes to reverse liver fibrosis
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“The TCA cycle is central to cellular energy metabolism and metabolic regulation (He et al. 2004).”
Self-citationEmerging roles of the metabolite succinate in bone-related diseases
Wu, Z., Dai, Q., Wang, Y., Wu, N., Wang, C., & Shi, J. (2025) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2400406 · Cited by 11
“The selectivity of SUCNR1 for succi ‐ nate is mediated by four positively charged key resi ‐ dues in the binding cavity enclosed by the seven trans ‐ membrane domains of the receptor, namely Arg99, His103, Arg252, and Arg281 (He et al., 2004).”
Mitochondria as Inducers of Neutrophil Extracellular Traps
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“During cellular stress, elevated succinate acts as a context-dependent DAMP by binding to SUCNR1 on immune and non-immune cells, triggering Ca²⁺ flux and PKC activation [116 ].”
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“The half-maximal effective response for GPR91 is obtained with succinate concentrations at 28–56 μM [34].”
BackgroundCórdoba‐Jover, B., Ribera, J., Portolés, I., Lecue, E., Rodríguez‐Vita, J., Pérez‐Sisqués, L., Mannara, F., Solsona‐Vilarrasa, E., García‐Ruiz, C., Fernández-Checa, J. C., et al. (2023) · Liver International · doi:10.1111/liv.15640 · Cited by 8
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“detected GPR91 mRNA levels in various nephron segments and juxtaglomerular apparatus (JGA) by RT-PCR and in situ hybridization (He et al. 2004).”
BackgroundMethodInfluentialImaging of Hypoxia in Retinal Vascular Disease
Feenstra, D. J., Drawnel, F., & Jayagopal, A. (2018) · InTech eBooks · doi:10.5772/intechopen.72252 · Cited by 8
“GPR91 regulates VEGF production in retinal ganglion cells via mitogen-activated protein kinase and prostaglandin signaling [32, 33] which contributes to the neovascular response following hypoxia [34].”
BackgroundTissue-Specific Peculiarities of Vibration-Induced Hypoxia in Rabbit Liver and Kidney
Vorobieva, V. V., & Шабанов, П. Д. (2019) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-019-04583-0 · Cited by 8
Moyon, A., Garrigue, P., Balasse, L., Fernandez-Sauze, S., Brige, P., Bouhlel, A., Hache, G., Dignat‐George, F., Taïeb, D., & Guillet, B. A. (2021) · Cells · doi:10.3390/cells10040795 · Cited by 8
“These effects are related to paracrine effects via an extracellular G-protein-coupled receptor named succinate receptor 1 (SUCNR1/GPR91) [4].”
BackgroundAKG/OXGR1 promotes skeletal muscle blood flow and metabolism by relaxing vascular smooth muscle
Yang, J., Xu, G., Xu, Y., Luo, P., Yuan, Y., Yao, L., Zhou, J., Zhu, Y., Gyawali, I., Xu, C. S., et al. (2022) · Life Metabolism · doi:10.1093/lifemeta/loac026 · Cited by 7
“As the cell membrane is impermeable to AKG, the effects of extracellular AKG are mostly mediated by its receptor 2-oxoglutarate receptor (OXGR1), while the OXGR1 mRNA expression is lower in skeletal muscle than in other tissues, such as the testis and kidneys [9].”
Molecular activation and G protein coupling selectivity of human succinate receptor SUCR1
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Self-citationMolecular basis of ligand recognition and activation of the human succinate receptor SUCR1
Li, C., Liu, H., Li, J., He, X., Zhu, H., Fu, W., & Xu, H. E. (2024) · Cell Research · doi:10.1038/s41422-024-00984-7 · Cited by 7
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“…the third trimester between GDM and control are lost in the peripartum period, in which there is a marked increase in succinate levels in maternal and fetal blood, reaching concentrations capable of physiologically activating the SUCNR1 receptor and inducing downstream signalling (He et al., 2004).”
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Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator
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InfluentialYang, X., Yao, S., An, J., Jin, H. D., Wang, H., & Tuo, B. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12385 · Cited by 7
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“The impact of Krebs cycle intermediates (citrate, itaconate, succinate, fumarate, and alpha-ketoglutarate) on the macrophage polarization is described in detail in [65, 66].”
A fluorescence ‘turn-on’ detection of α-ketoglutaric acid with silole as the fluorescence reporter
Zhan, C., Zhang, G., & Zhang, D. (2017) · Journal of Photochemistry and Photobiology A Chemistry · doi:10.1016/j.jphotochem.2017.08.017 · Cited by 6
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Chukanova, E. I., Сергеевна, Ч. А., & Radionova, D. M. (2022) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202212208135 · Cited by 7
Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation
Duncan, E. M., Vita, L., Dibnah, B., & Hudson, B. D. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1197102 · Cited by 7
“Initial expression studies found high levels of SUCNR1 in kidney, liver and spleen (78), while the receptor has also been found in adipose (80), and in various immune cells including dendritic cells and macrophages (81).”
BackgroundMühling, J., Tiefenbach, M., López‐Barneo, J., Piruat, J. I., García‐Flores, P., Pfeil, U., Gries, B., Mühlfeld, C., Weigand, M. A., Kummer, W., et al. (2010) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2010.09.023 · Cited by 7
Lukyanova, L. D., Kirova, Y. I., & Germanova, E. L. (2016) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-016-3299-0 · Cited by 7
Wei, B., Wang, C., Teng, T., Guo, P., Chen, M., Xia, F., Liu, H., Xie, J., Feng, J., & Huang, H. (2020) · Gland Surgery · doi:10.21037/gs-20-202 · Cited by 7
“In the development of tumor, amino acid metabolism is also closely related to tumor production through TCA cycle (43,44).”
BackgroundOxidative Stress and Protein Oxidation
Grune, T., Catalgol, B., & Jung, T. (2012) · Wiley eBooks · doi:10.1002/9781118493038.ch1 · Cited by 7
Zhang, J., Qin, B., Song, L., & Hong, H. (2024) · Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy · doi:10.1016/j.saa.2024.125222 · Cited by 6
The Link Between Dietary Timing and Exercise Performance Through Adipocyte AMPKα2 Signaling
Kim, S., Baek, J., & Kim, M. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136061 · Cited by 6
“Extracellular succinate binds to specific G-protein-coupled receptors (GPCRs), particularly SUCNR1, and activates downstream signaling cascades that influence gene expression [50].”
Cellular Metabolites Regulate Central Nucleic Acid Sensing Pathways
Blay‐Cadanet, J., Pedersen, A., & Holm, C. K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.635738 · Cited by 6
“(28), that succinate can activate extracellular signal-regulated kinase (Erk), a downstream component of the TLR pathways.”
BackgroundVerlander, J. W., Lee, H., Wall, S. M., Harris, A. N., & Weiner, I. D. (2022) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00175.2022 · Cited by 6
Class A Orphans in GtoPdb v.2023.1
Alexander, S. P. H., Battey, J., Benson, H. E., Benya, R. V., Bonner, T. I., Davenport, A. P., Singh, K. D., Eguchi, S., Harmar, A. J., Holliday, N. D., et al. (2023) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f16/2023.1 · Cited by 6
Development and Characterization of Potent Succinate Receptor Fluorescent Tracers
Ciba, M., Dibnah, B., Hudson, B. D., & Ulven, E. R. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00552 · Cited by 6
Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells
Le, C. T., Nguyen, G., Park, S. Y., Dong, H. N., Cho, Y. K., Lee, J., Im, S., Choi, D.-H., & Cho, E.-H. (2023) · Endocrinology and Metabolism · doi:10.3803/enm.2023.1661 · Cited by 6
“Succinate and its receptor have been linked to several pathological processes such as hypertension [4,5], diabetes and obesity [6-9].”
BackgroundTrailblazing in adjuvant research: succinate’s uncharted territory with neutrophils
Wang, Y., Xiu, Z., Qu, K., Wang, L., Wang, H., & Yu, Y. (2024) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00129.2024 · Cited by 6
Identification of lead compounds for 99mTc and 18F GPR91 radiotracers
Klenc, J., Lipowska, M., & Taylor, A. T. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.04.015 · Cited by 6
Wang, Y., Liu, X., Laurini, E., Posocco, P., Ziarelli, F., Fermeglia, M., Qu, F., Pricl, S., Zhang, C., & Peng, L. (2014) · Organic & Biomolecular Chemistry · doi:10.1039/c4ob00630e · Cited by 6
Gupta, A. K., Kumar, S., Kashyap, S., Kumar, D., & Kapoor, A. (2016) · The Journal of Applied Laboratory Medicine · doi:10.1373/jalm.2016.020776 · Cited by 7
“A recent study revealed that succinate, the tricarboxylic acid (TCA) cycle intermediate, may stimulate Gprotein–coupled receptors in the kidney to regulate blood pressure (6).”
BackgroundInhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium
Lim, R., & Lappas, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/6454282 · Cited by 6
“GPR91 is considered to be a class A orphan GPCR; however, under some circumstances, the Krebs cycle intermediate succinate can serve as a ligand for GPR91 [9], and thus, it is also known as succinate receptor 1, SUCNR1.”
BackgroundStrutynska, N. A., Strutynskyi, R. B., Chorna, S. V., Semenykhina, O. M., Mys', L., Moibenko, O. O., & Sahach, V. F. (2014) · Fìzìologìčnij žurnal · doi:10.15407/fz59.06.003 · Cited by 6
Eliasen, A. M., Chin, M. R., Axelrod, A. J., Abagyan, R. A., & Siegel, D. R. (2018) · Tetrahedron · doi:10.1016/j.tet.2018.02.068 · Cited by 6
Васин, М. В., Ушаков, И. Б., & Bukhtiyarov, I. V. (2018) · Biology Bulletin · doi:10.1134/s1062359017060115 · Cited by 6
“The effect of succinate is realized through the cell receptor GPR91 with the involvement of the PI3K/Akt signaling pathway (Wittenberger et al., 2001; He et al., 2004; Yang et al., 2014).”
Hyperactivation of succinate dehydrogenase in lymphocytes of newborn rats
Khunderyakova, N. V., Zakharchenko, M. V., Zakharchenko, A. V., & Kondrashova, M. N. (2008) · Biochemistry (Moscow) · doi:10.1134/s0006297908030152 · Cited by 6
An Orphan Receptor Adopted by a Family of Transmitters
Civelli, O. (2004) · Molecular Pharmacology · doi:10.1124/mol.104.010348 · Cited by 6
“GPRC6A was one of the orphan GPCRs; its highest degree of sequence similarity was not to a human receptor but instead to one from goldfish called 5.24 (Speca et al., 1999), which was known to sense basic amino acids, potent odorants in fish.”
BackgroundInfluentialNv, B., Bairamov, I. T., Olenin, A. Y., Хабиб, О. Н., & Fedotcheva, N. I. (2013) · Global Journal of Pathology and Microbiology · Cited by 6
Yao, X., Liu, H., Duan, C., Zhang, Y., Wu, X., Li, B., Li, S., Gong, Y. Q., Liu, T., Wang, X., et al. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70450 · Cited by 5
“34,35 Further investigation is warranted to determine whether SDH restriction and increased succinate accumulation amplify the pro-inflammatory effect of SUCNR1.”
Prevotella copri promotes white adipose browning and ameliorates adiposity
Liu, S., Li, H., Li, R., Chang, Y., Wang, S., Wang, Z., Sun, Y., Li, M., Liu, M., Zhou, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67327-x · Cited by 6
Self-citationZhang, X., Long, L., He, Y., Yang, H., Jiang, G., Yao, T., Jiang, M., Cheng, X., & Meng, J. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116213 · Cited by 5
Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme
Mailloux, R. J. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.02.050 · Cited by 5
Ligand Recognition and Activation Mechanism of the Alicarboxylic Acid Receptors
Liu, Y., Zhou, Z., Guan, F., Han, Z., Zhu, C., Ye, S., Yu, X., & Qiao, A. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168795 · Cited by 5
GPR91: EXPANDING THE FRONTIERS OF KREBS CYCLE INTERMEDIATES
Fonseca, M. D. C., Aguiar, C. J., Franco, J. A. D. R., Gingold, R. N., & Leite, M. F. (2017) · Nephrology (Saint-Petersburg) · doi:10.24884/1561-6274-2017-21-1-9-18 · Cited by 5
Louer, E., Lorés‐Motta, L., Ion, A. M., den Hollander, A. I., & Deen, P. M. T. (2019) · RNA Biology · doi:10.1080/15476286.2019.1643100 · Cited by 5
“Consequently, SUCNR1 modulators are considered as highly promising novel pharmaceuticals to treat these common diseases [2].”
Background
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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