GPR91: EXPANDING THE FRONTIERS OF KREBS CYCLE INTERMEDIATES
https://doi.org/10.24884/1561-6274-2017-21-1-9-18
Abstract
Since it was discovered, the citric acid cycle has been known to be central to cell metabolism and energy homeostasis. Mainly found in the mitochondrial matrix, some of the intermediates of the Krebs cycle are also present in the blood stream. Currently, there are several reports that indicate functional roles for Krebs intermediates out of its cycle. Succinate, for instance, acts as an extracellular ligand by binding to a G-protein coupled receptor, known as GPR91, expressed in kidney, liver, heart, retinal cells and possibly many other tissues. Succinate activated GPR91 induces a wide array of physiological and pathological effects. Through GPR91, succinate is involved in functions such as regulation of blood pressure, inhibition of lipolysis in white adipose tissue, development of retinal vascularization, cardiac hypertrophy and activation of stellate hepatic cells by ischemic hepatocytes. Current review is dedicated to discussion of these effects.
About the Authors
M. de C. Fonseca
Federal University of Minas Gerais
Brazil
Brazil
Department of Physiology and Biophysics
Av. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901
C. J. Aguiar
Centro Universitário Estácio de Sá, Belo Horizonte, MG
Brazil
Brazil
J. A. da Rocha Franco
Federal University of Minas Gerais
Brazil
Brazil
Department of Physiology and Biophysics
Av. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901
R. N. Gingold
Federal University of Minas Gerais
Brazil
Brazil
Department of Physiology and Biophysics
Av. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901
M. F. Leite
Federal University of Minas Gerais
Brazil
Brazil
Department of Physiology and Biophysics
Av. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901
References
1. Thunberg T. Zur Kenntnis des intermediären Stoffwechsels und der dabei wirksamen. Enzyme Skandinavisches Archiv für Physiologie 1920;40:1–91. doi: 10.1111/j.1748-1716.1920.tb01412.x
2. Annan G, Banga I, Blazsó A et al. Über die Bedeutung der Fumarsäure für die tierische Gewebeatmung. Einleitung, übersicht, Methoden Hoppe-Seyler’s Zeitschrift für Physiologische Chemie 1935;236:1–20
3. Krebs HA, Johson WA. The role of citric acid in intermediate metabolism in animal tissues. Enzymologia 1937;4:148–156
4. Krebs HA. The history of the tricarboxylic acid cyle. Perspect Biol Med. 1970;14:154–170 5. Fedotcheva NI, Sokolov AP, Kondrashova MN. Nonenzymatic formation of succinate in mitochondria under oxidative stress. Free Radic Biol Med 2006;41:56–64. doi: 10.1016/j.freeradbiomed.2006.02.012
5. Brosnan JT, Krebs HA, Williamson DH. Effects of Ischaemia on Metabolite Concentrations in Rat Liver. Biochent J 1970;117:91–96. doi: 10.1042/bj1170091
6. Taegtmeyer H. Metabolic responses to cardiac hypoxia. Increased production of succinate by rabbit papillary muscles. Circ Res 1978;43:808–815
7. Chouchani ET, Pell VR, Gaude E et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014;515(7527):431–435. doi: 10.1038/nature13909
8. Knauf F, Rogina B, Jiang Z et al. Functional characterization and immunolocalization of the transporter encoded by the lifeextending gene Indy. Proc Natl Acad Sci USA 2002;99:14315– 14319. doi: 10.1073/pnas.222531899
9. Inoue K, Fei YJ, Zhuang L et al. Functional features and genomic organization of mouse NaCT, a sodium-coupled transporter for tricarboxylic acid cycle intermediates. Biochem J 2004;378:949–957. doi: 10.1042/BJ20031261
10. He W, Miao FJ, Lin DC et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 2004;429(6988):188–193. doi: 10.1038/nature02488
11. Ariza AC, Deen PM, Robben JH. The succinate receptor as a novel therapeutic target for oxidative and metabolic stressrelated conditions. Front Endocrinol 2012;00022:1664–2392
12. Bhuniya D, Umrani D, Dave B et al. Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg Med Chem Lett 2011;21(12):3596–3602. doi: 10.1016/j.bmcl.2011.04.091
13. Hakak Y, Lehmann-Bruinsma K, Phillips S et al. The role of the GPR91 ligand succinate in hematopoiesis. J Leukoc Biol 2009;85:837–843. doi: 10.1189/jlb.1008618
14. Aguiar CJ, Rocha-Franco JA, Sousa PA et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun Signal 2014;12(1):78. doi: 10.1186/s12964-014-0078-2
15. Toma I, Kang JJ, Sipos A et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest 2008;118:2526–2534. doi: 10.1172/JCI33293
16. Vargas SL, Toma I, Kang JJ et al. Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J Am Soc Nephrol 2009;20(5):1002–11. doi: 10.1681/ASN.2008070740
17. Robben JH, Fenton RA, Vargas SL et al. Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int 2009;76(12):1258–1267. doi: 10.1038/ki.2009.360
18. Correa PRAV, Krulog EA, Thompsom M et al. Succinate is a paracrine signal for liver damage. J Hepatology 2007;47:262–269. doi: 10.1016/j.jhep.2007.03.016
19. Sapieha P, Sirinyan M, Hamel D et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 2008;14(10):1067–1076. doi: 10.1038/nm.1873
20. Rubic T, Lametschwandtner G, Jost S et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 2008;9:1261–1269. doi: 10.1038/ni.1657
21. Macaulay IC, Tijssen MR, Thijssen-Timmer DC et al. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood 2007;109:3260– 3269. doi: 10.1182/blood-2006-07-036269
22. Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000;275(4):2247–2250
23. Li YH, Woo SH, Choi DH, Cho EH. Succinate causes a-SMA production through GPR91 activation in hepatic stellate cells. Biochem Biophys Res Commun 2015;463:853–858. doi: 10.1016/j.bbrc.2015.06.023
24. Adair TH, Gay WJ, Montani JP. Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 1990;259:393–404
25. Folbergrova J, Ljunggren B, Norberg K, Siesjo BK. Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates, and associated amino acids in the rat cerebral cortex. Brain Res 1974;80:265–279
26. Hoyer S, Krier C. Ischemia and aging brain. Studies on glucose and energy metabolism in rat cerebral cortex. Neurobiol Aging 1986;7:23–29
27. Joyal JS, Sitaras N, Binet F et al. Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood 2011;117:6024–6035. doi: 10.1182/blood-2010-10-311589
28. Hu J, Wu Q, Li T et al. Inhibition of high glucose-induced VEGF release in retinal ganglion cells by RNA interference targeting G protein-coupled receptor 91. Exp Eye Res 2013;109:31–39. doi: 10.1016/j.exer.2013.01.011
29. Hu J, Li T, Du S et al. The MAPK signaling pathway mediates the GPR91-dependent release of VEGF from RGC-5 cells. Int J Mol Med 2015;36(1):130–138. doi: 10.3892/ijmm.2015.2195
30. Sadagopan N, Li W, Roberds SL et al. Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens 2007;20(11):1209–1215. doi: 10.1016/j.amjhyper.2007.05.010
31. McCreath KJ, Espada S, Gálvez BG et al. Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity. Diabetes 2015;64(4):1154–1167. doi: 10.2337/db14-0346
32. Aguiar CJ, Andrade VL, Gomes ER et al. Succinate modulates Ca(2+) transient and cardiomyocyte viability through PKA-dependent pathway. Cell Calcium 2010;47(1):37–46. doi: 10.1016/j.ceca.2009.11.003
33. Zucker AR, Gondolesi GE, Abbott MA et al. Liver-intestine transplant from a pediatric donor with unrecognized mitochondrial succinate cytochrome C reductase deficiency. Transplantation 2005;79(3):356–358
34. Davili Z, Johar S, Hughes C et al. Succinate dehydrogenase deficiency associated with dilated cardiomyopathy and ventricular noncompaction. Eur J Pediatr 2007;166:867–870. doi: 10.1007/s00431-006-0310-1
Review
For citations:
de C. Fonseca M., Aguiar C.J., da Rocha Franco J.A., Gingold R.N., Leite M.F. GPR91: EXPANDING THE FRONTIERS OF KREBS CYCLE INTERMEDIATES. Nephrology (Saint-Petersburg). 2017;21(1):9-18. (In Russ.) https://doi.org/10.24884/1561-6274-2017-21-1-9-18
Views:
2230
Email this article 