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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]
Citations
Cites
(1975) · Journal of AOAC INTERNATIONAL · doi:10.1093/jaoac/58.5.1085 · Cited by 20,078
(1974) · Elsevier eBooks · doi:10.1016/b978-0-12-091304-6.x5001-0 · Cited by 6,786
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Palczewski, K., Kumasaka, T., Hori, T., Behnke, C. A., Motoshima, H., Fox, B. A., Trong, I. L., Teller, D. C., Okada, T., Stenkamp, R. E., et al. (2000) · Science · doi:10.1126/science.289.5480.739 · Cited by 5,637
IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK
Woronicz, J. D., Gao, X., Cao, Z., Rothe, M., & Goeddel, D. V. (1997) · Science · doi:10.1126/science.278.5339.866 · Cited by 1,183
Morphology, physiology, and molecular biology of renin secretion
Hackenthal, E., Paul, M., Ganten, D., & Taugner, R. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.4.1067 · Cited by 614
A Noninvasive Computerized Tail-Cuff System for Measuring Blood Pressure in Mice
Krege, J. H., Hodgin, J. B., Hagaman, J. R., & Smithies, O. (1995) · Hypertension · doi:10.1161/01.hyp.25.5.1111 · Cited by 587
Minireview: Overview of the Renin-Angiotensin System—An Endocrine and Paracrine System
Lavoie, J. L., & Sigmund, C. D. (2003) · Endocrinology · doi:10.1210/en.2003-0150 · Cited by 576
A role for mitochondrial enzymes in inherited neoplasia and beyond
Eng, C., Kiuru, M., Fernandez, M. J., & Aaltonen, L. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1013 · Cited by 392
Chuang, P., Kawcak, T., & McMahon, A. P. (2003) · Genes & Development · doi:10.1101/gad.1026303 · Cited by 316
Effects of ischaemia on content of metabolites in rat liver and kidney in vivo
HEMS, D. A., & Brosnan, J. T. (1970) · Biochemical Journal · doi:10.1042/bj1200105 · Cited by 237
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“Another potential mechanism linking fumarate with AMPK activation is the involvement of G-protein-coupled receptors (GPCRs) (22).”
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“Recent progress in extracellular succinate function has been facilitated by the discovery of the succinate receptor SUCNR1 [64].”
Sabadell‐Basallote, J., Astiarraga, B., Castaño, C., Ejarque, M., Repollés-de-Dalmau, M., Quesada, I., Blanco, J., Núñez‐Roa, C., Rodríguez‐Peña, M., Martínez, L., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci173214 · Cited by 32
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“180”
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“Succinate, which activates GPR91, acutely increases circulating Ang II (angiotensin II) and BP in rats.(22) Like GPR81, GPR91 is also coupled to G i , and Figure 3.”
BackgroundSuccinate metabolism in the retinal pigment epithelium uncouples respiration from ATP synthesis
Hass, D. T., Bisbach, C. M., Robbings, B. M., Kamat, V., Sadı́lek, M., Sweet, I. R., & Hurley, J. B. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110917 · Cited by 34
“The EC 50 of SUCNR1 for succinate 4.5–56 μM ( Geubelle et al., 2017; He et al., 2004), and we use far higher concentrations of extracellular succinate in our experiments.”
InfluentialArachidonic Acid Metabolites and the Kidney
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Aleshin, V. A., Mkrtchyan, G. V., Kaehne, T., Graf, A. V., Maslova, M. V., & Bunik, V. I. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14951 · Cited by 33
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“Succinate can also act cell-extrinsically by signaling through its receptor GPR91 [71], leading to production of pro-inflammatory cytokines in DCs [139].”
BackgroundPierzynowski, S. G., & Pierzynowska, K. G. (2022) · Advances in Medical Sciences · doi:10.1016/j.advms.2022.02.004 · Cited by 30
Wang, L., Zhang, Y., Kiprowska, M., Guo, Y., Yamamoto, K., & Li, X. (2020) · Metabolites · doi:10.2139/ssrn.3565017 · Cited by 30
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The flux of energy in critical illness and the obesity paradox
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Succinate reversesin-vitroplatelet inhibition by acetylsalicylic acid and P2Y receptor antagonists
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“Succinate is a citric acid cycle intermediate that has recently been shown to regulate, via activation of its proposed membrane surface receptor SUCNR1 (GPR91), cellular functions relevant to immunity [16], hyperglycemia [17], hypertension [18, 19], retinal neovascularization [20], and ischemic liver injury [21].”
BackgroundLuciano‐Mateo, F., Cabré, N., Fernández‐Arroyo, S., Baiges‐Gayà, G., Hernández‐Aguilera, A., Rodríguez‐Tomàs, E., Muñoz‐Pinedo, C., Menéndez, J. A., Camps, J., & Joven, J. (2020) · Scientific Reports · doi:10.1038/s41598-020-68769-7 · Cited by 30
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Park, S., Kim, O., Lee, K., Park, I. B., Kim, N. H., Moon, S., Im, J.-B., Sharma, S. P., Oh, B., Nam, S., et al. (2022) · Genomics · doi:10.1016/j.ygeno.2022.110407 · Cited by 29
Guo, L.-J., Chen, S., Ou, L., Li, S., Ye, Z.-N., & Liu, J. (2022) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s369090 · Cited by 34
“The AKG receptor is denominated as OXGR1, which is also known as GPR99 or GPR80, and predominantly expressed in the renal distal tubules.(30,31) In terms of absorption and transportation in vivo, AKG is freely filtered in the glomerulus and actively reabsorbed in the proximal tubule and Henle’s loop, as well as gut, e…”
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“In contrast, there is now convincing evidence that GPR80/99 binds a-ketoglutarate, thereby functioning as receptor for citric acid cycle intermediates [121].”
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“20 are active signaling molecules (He et al., 2004; Gonzalez et al., 2004).”
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“Interestingly, OXGR1/GPR99 was once inappropriately suggested to be a P2Y15 receptor (3), but aside from that, there are practically no studies on the interaction between a-KG/ OXGR1 system and other intrarenal signaling systems.”
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Guo, W., Jiang, C., Liu, Y., Li, T., Liu, X., Jin, M., Qu, K., Chen, H., Jin, X., Liu, H., et al. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.6b00179 · Cited by 29
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“…for the presence of a factor that could activate a receptor, and then fractionated the extract until the compound was pure enough to identify (Civelli et al., 2013; Devane et al., 1992; He et al., 2004; Kojima et al., 1999; Reinscheid et al., 1995; Sakurai et al., 1998; Shimomura et al., 2002).”
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“Furthermore, the recent deorphanization of severalGPRs [apelin receptor (17, 18),Gpr4 (19–21),Gpr30 (22–24), Gpr41 and Gpr43 (9, 25, 26), Gpr48 (27–31), and Gpr99 (16, 32, 33)] and investigation of their renal-specific functionhave established thatnovelGPCRsandmetabolic intermediates of known pathways are involved in…”
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Self-citationSuccinate, increased in metabolic syndrome, activates GPR91 receptor signaling in urothelial cells
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Pulmonary neuroendocrine cells sense succinate to stimulate myoepithelial cell contraction
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“Previous reports showed that activating SUCNR1 increases the intracellular Ca 2+ concentration, [Ca 2+ ] c (He et al., 2004; Robben et al., 2009; Wang et al., 2019).”
The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids
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“The demonstration that GPR91 is a succinate receptor and GPR80/GPR99 a receptor for a-ketoglutarate is very strong [10].”
BackgroundInfluentialCalcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate
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“In 2004, the formerly orphan Gi- and Gqcoupled cell surface receptor GPR91 was found to specifically bind the citric acid cycle intermediate succinate [20].”
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“[68] have demonstrated that succinate can stimulate GPR91 and lead to accumulation of inositol triphosphate, calcium mobilization, and extracellular signal regulation kinase (ERK) phosphorylation.”
BackgroundLättig, J., Oksche, A., Beyermann, M., Rosenthal, W., & Krause, G. (2009) · Journal of Peptide Science · doi:10.1002/psc.1146 · Cited by 28
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Tatke, G., Kumari, H., Silva‐Herzog, E., Ramirez, L., & Mathee, K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0129629 · Cited by 27
“It is known that TCA cycle intermediates (C4, C5, and C6 dicarboxylates) are present at micromolar (μM) concentrations in blood that increase with tissues damaged [26,92].”
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“SUCNR1 is a Gi/oor Gq-coupled receptor [68] and succinate, but no other intermediate of the TCA cycle is able to activate the receptor, with EC50 values of 30–50 μM being in the same range as the physiological plasma concentrations during exercise [68].”
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“Furthermore, succinic acid has been reported to increase blood pressure in animals by activating its receptor G-protein coupled receptor 91 (GPR91), proposing a potential role of succinate in hypertension-related diseases, including ischemia and atherosclerosis [36].”
BackgroundChen, H., Laurent, S., Bédu, S., Ziarelli, F., Chen, H.-L., Cheng, Y., Zhang, C., & Peng, L. (2006) · Chemistry & Biology · doi:10.1016/j.chembiol.2006.06.009 · Cited by 27
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“[46] recently discovered that the “orphan” G-protein– coupled receptors GPR91 and GPR99, which are highly expressed in the kidney, bind the tricarboxylic acid cycle intermediates succinate and α-ketoglutarate, respectively.”
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“OXGR1 was first regarded as an orphan receptor, but He and colleagues have identified it as a receptor for a-ketoglutarate, a citric acid cycle (CAC) intermediate [9].”
BackgroundG protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases
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Ulven, E. R., Trauelsen, M., Brvar, M., Lückmann, M., Bielefeldt, L. Ø., Jensen, L. K. I., Schwartz, T. W., & Frimurer, T. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-28263-7 · Cited by 26
The intestine is a major contributor to circulating succinate in mice
Tong, W., Hannou, S. A., Wang, Y., Astapova, I. I., Sargsyan, A., Monn, R., Thiriveedi, V., Li, D., McCann, J. R., Rawls, J. F., et al. (2022) · The FASEB Journal · doi:10.1096/fj.202200135rr · Cited by 26
“Second, the models used to compare the relative rates of succinate absorption versus endogenous production relies on several assumptions which include: (1) the assumption that the metabolism of absorbed and endogenously produced succinate follows first- order kinetics and (2) the assumption that recirculation of label…”
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Yang, L., Yu, D., Fan, H.-H., Yu, F., Hu, L., Zhang, W., Zhou, K., & Mo, X. (2014) · PubMed Central · Cited by 26
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“Extracellular succinate function is achieved by binding its specific G protein-coupled receptor succinate receptor 1 (SUCNR1/GPR91) (He et al., 2004).”
BackgroundThe Sensing Liver: Localization and Ligands for Hepatic Murine Olfactory and Taste Receptors
Kurtz, R., Steinberg, L. G., Betcher, M. C., Fowler, D., & Shepard, B. D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.574082 · Cited by 25
Tumour microenvironment in pheochromocytoma and paraganglioma
Martinelli, S., Amore, F., Canu, L., Maggi, M., & Rapizzi, E. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1137456 · Cited by 26
Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy
Matsumoto, M., Suzuma, K., Maki, T., Kinoshita, H., Tsuiki, E., Fujikawa, A., & Kitaoka, T. (2012) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2011.10.006 · Cited by 25
Regulation of neuronal ion channels via P2Y receptors
Lechner, S. G., & Boehm, S. (2004) · Purinergic Signalling · doi:10.1007/s11302-004-4746-3 · Cited by 25
“The presumed P2Y15 receptor is also activated by a-ketoglutarate [10] and may thus not be a true member of the P2Y family.”
BackgroundCitric Acid in Drug Formulations Causes Pain by Potentiating Acid-Sensing Ion Channel 1
Yang, Y. L., & Lai, T. W. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2087-20.2021 · Cited by 25
The known and new ideas about the mechanism of action and the spectrum of effects of Mexidol
Воронина, Т. А., Литвинова, С. А., Гладышева, Н. А., & Вадимович, Ш. А. (2025) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202512505122 · Cited by 28
Dai, M., Bu, S., & Miao, Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1630310 · Cited by 26
“…on macrophages, dendritic cells, intestinal epithelial cells, kidneys, liver, and adipose tissue, engages succinate to launch pro-in fl ammatory cascades involving NF-k B and MAPK signaling (8), thereby serving as a metabolic checkpoint linking succinate accumulation to IBD pathogenesis (9, 10).”
Witowski, N. E., Lusczek, E. R., Determan, C. E., Lexcen, D. R., Mulier, K. E., Ostrowski, B. G., & Beilman, G. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124467 · Cited by 24
Pheochromocytomas and Paragangliomas as Causes of Endocrine Hypertension
Canu, L., Parenti, G., Filpo, G. D., & Mannelli, M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00333 · Cited by 24
“Succinate, which is increased in SDHx mutated PPGL, causes an increase of plasma renin activity in rats (17) but circulating succinate does not differ between hypertensive patients and normotensive controls (18).”
BackgroundAtallah, R., Gindlhuber, J., Platzer, W., Bärnthaler, T., Tatzl, E., Toller, W. G., Strutz, J., Rittchen, S., Luschnig, P., Birner‐Gruenberger, R., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222112048 · Cited by 23
“hy926 (ATCC, Virginia, USA) at passages (13-17) were cultured as mentioned before in DMEM supplemented with 10% FBS, 1% P/S and 1% HAT media supplement (ThermoFisher Scientific).”
BackgroundMethodChen, P., Xu, Z.-H., Huang, Y., Luo, Y., Zhu, D., Wang, P., Du, Z., Yang, Y., Wu, D., Lai, W., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.07.018 · Cited by 24
SNPs in Genes Encoding G Proteins in Pharmacogenetics
Klenke, S., & Siffert, W. (2011) · Pharmacogenomics · doi:10.2217/pgs.10.203 · Cited by 24
Morla, L. (2016) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v7.i1.44 · Cited by 24
He, X., Liu, Y., Usa, K., Tian, Z., Cowley, A. W., & Liang, M. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00073.2014 · Cited by 24
“Intravenous infusion of succinate, an intermediate in the tricarboxylic acid cycle, or inducible overexpression of uncoupling protein 1 in vascular smooth muscle cells, which uncouples respiration and oxidative phosphorylation, caused hypertension in mice (2, 10).”
BackgroundDai, X., Hao, J., Gu, J., & Li, Y. (2020) · ACS Applied Bio Materials · doi:10.1021/acsabm.0c00378 · Cited by 24
Inhibition of the Na+/Dicarboxylate Cotransporter by Anthranilic Acid Derivatives
Pajor, A. M., & Randolph, K. M. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.035352 · Cited by 24
Arg333 and Arg334 in the COOH terminus of the human P2Y1 receptor are crucial for Gq coupling
Ding, Z., Tuluc, F., Bandivadekar, K. R., Zhang, L., Jin, J., & Kunapuli, S. P. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00401.2004 · Cited by 24
“However, the P2Y15 receptor might indeed be a receptor for -ketoglutarate (23).”
BackgroundGaggin, H. K., Bhardwaj, A., Belcher, A. M., Motiwala, S. R., Gandhi, P. U., Simon, M. L., Kelly, N. P., Anderson, A. M., Garasic, J. M., Danik, S. B., et al. (2014) · IJC Metabolic & Endocrine · doi:10.1016/j.ijcme.2014.08.005 · Cited by 23
“Indeed, a growing body of data suggests unanticipated roles for metabolites in various physiological responses, including a role for tryptophan metabolites in inflammation and citric acid cycle intermediates in blood pressure control and lipolysis [49,50].”
BackgroundSuccinate-SUCNR1 induces renal tubular cell apoptosis
Pu, M., Zhang, J., Zeng, Y., Hong, F., Qi, W., Yang, X., Gao, G., & Zhou, T. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00327.2022 · Cited by 25
GPR80/99, proposed to be the P2Y15 receptor activated by adenosine and AMP, is not a P2Y receptor
Qi, A., Harden, T. K., & Nicholas, R. A. (2004) · Purinergic Signalling · doi:10.1007/s11302-004-5069-0 · Cited by 23
“Nature 2004; 429: 188–93 [15]) reported that GPR80 is a Gq-coupled receptor activated by the citric acid cycle intermediate, aketoglutarate.”
BackgroundMethodInfluentialKinoshita, H., Suzuma, K., Maki, T., Maekawa, Y., Matsumoto, M., Kusano, M., Uematsu, M., & Kitaoka, T. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-13839 · Cited by 23
Paddenberg, R., Tiefenbach, M., Faulhammer, P., Goldenberg, A., Gries, B., Pfeil, U., Lips, K. S., Piruat, J. I., López‐Barneo, J., SCHERMULY, R. T., et al. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvr359 · Cited by 22
The nature of early astroglial protection—Fast activation and signaling
Kardos, J., Héja, L., Jemnitz, K., Kovács, R., & Palkovits, M. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.005 · Cited by 23
Zhang, H., Zheng, J., Lin, J., Chen, J., Yu, Z., Chen, C., & Liu, T. (2018) · Gene · doi:10.1016/j.gene.2018.04.029 · Cited by 23
Self-citationReceptors of intermediates of carbohydrate metabolism, GPR91 and GPR99, mediate axon growth
Cherif, H., Duhamel, F., Cécyre, B., Bouchard, A., Quintal, A., Chemtob, S., & Bouchard, J. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2003619 · Cited by 25
Lückmann, M., Trauelsen, M., Frimurer, T. M., & Schwartz, T. W. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.12.005 · Cited by 23
Stagliano, M. C., DeKeyser, J. G., Omiecinski, C. J., & Jones, A. D. (2010) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.4796 · Cited by 23
Dias, G. G., Souto, F. T., & Machado, V. G. (2024) · Chemosensors · doi:10.3390/chemosensors12080156 · Cited by 22
Wang, Y. Y., Wang, Y., Qi, X.-Y., Liao, Z., Mai, Y.-N., & Xiao, X. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.839849 · Cited by 24
“Similar to SCFAs, gut microbiota-derived succinate is akin to hormones by engaging succinate receptor 1 (SUCNR1) (63).”
BackgroundInfluentialBasic Mechanisms of Immunometabolites in Shaping the Immune Response
Ryan, D. G., Peace, C. G., & Hooftman, A. (2023) · Journal of Innate Immunity · doi:10.1159/000535452 · Cited by 22
“Extracellular succinate is also able to act as an extracellular signal by activating the GPCR GPR91 which was an orphan receptor until 2004 [45].”
BackgroundShenol, A., Lückmann, M., Trauelsen, M., Lambrughi, M., Tiberti, M., Papaleo, E., Frimurer, T. M., & Schwartz, T. W. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.011 · Cited by 22
Chemical and Physical Sensors in the Regulation of Renal Function
Pluznick, J. L., & Caplan, M. J. (2014) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.00730114 · Cited by 22
“Therefore, inappropriate activation of the RAS in diabetes is likely tied to elevated plasma glucose, and as a consequence, elevated succinate levels, which activate Gpr91 (and, therefore, renin release).”
BackgroundInfluentialMitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines
Iacobazzi, V., Infantino, V., Castegna, A., Menga, A., Palmieri, E. M., Convertini, P., & Palmieri, F. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0260 · Cited by 21
“Moreover, succinate acts also as a ligand of SUCNR1, a succinate receptor highly expressed in kidney, liver, spleen small intestine (He et al., 2004), and dendritic cells (Rubic et al.”
BackgroundInfluentialRivera, J. C., Madaan, A., Zhou, T. E., & Chemtob, S. (2016) · Acta Paediatrica · doi:10.1111/apa.13586 · Cited by 22
“by which a tissue regulates its vascular density remained unknown until receptors for major Krebs cycle metabolites were discovered (32).”
BackgroundThe Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease
Recio, C., Lucy, D., Iveson, P., Iqbal, A. J., Valaris, S., Wynne, G. M., Russell, A. J., Choudhury, R. P., O’Callaghan, C. A., Monaco, C. G., et al. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7168 · Cited by 22
“The intriguing link between Krebs cycle intermediates and cell signaling, started with the pioneering work of He et al. , has played an important role in the emerging concept of immunometabolism (49).”
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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