[en] Background and Purpose
The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists.
Experimental Approach
We screened a library of succinate analogues and analysed their activity on SUCNR1. In addition, we modelled a pharmacophore and a binding site for the receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilisation, TGF-α shedding and recruitment of arrestin 3. The in vivo impact of SUCNR1 activation by these new agonists was evaluated on rat blood pressure.
Key Results
We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to the one of succinic acid. Interestingly, cis-epoxysuccinic acid was characterized by a 10 to 20 fold higher potency than succinate on the receptor. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM) as compared to succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all bioassays tested. In vivo, cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid increased rat blood pressure to the same extent as succinate did.
Conclusions and Implications
We provide new agonist tools for SUCNR1 that should facilitate further research on this understudied receptor.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol 172: 5744–5869.
Ballesteros J, Weinstein H (1995). Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors. Meth Neurosci 25: 366–428.
Bhuniya D, Umrani D, Dave B, Salunke D, Kukreja G, Gundu J et al. (2011). Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg Med Chem Lett 21: 3596–3602.
Bialy D, Wawrzynska M, Bil-Lula I, Krzywonos-Zawadzka A, Wozniak M, Cadete VJ et al. (2015). Low frequency electromagnetic field conditioning protects against I/R injury and contractile dysfunction in the isolated rat heart. Biomed Res Int 2015: 396593.
Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SP, Giembycz MA et al. (2015). Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol 172: 3461–3471.
Dilly S, Liegeois JF (2011). Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study. J Comput Aided Mol Des 25: 163–169.
Dogne S, Rath G, Jouret F, Caron N, Dessy C, Flamion B (2016). Hyaluronidase 1 deficiency preserves endothelial function and glycocalyx integrity in early streptozotocin-induced diabetes. Diabetes 65: 2742–2753.
Edwards AM, Isserlin R, Bader GD, Frye SV, Willson TM, Yu FH (2011). Too many roads not taken. Nature 470: 163–165.
Gilissen J, Jouret F, Pirotte B, Hanson J (2016). Insight into SUCNR1 (GPR91) structure and function. Pharmacol Ther 159: 56–65.
Hakak Y, Lehmann-Bruinsma K, Phillips S, Le T, Liaw C, Connolly DT et al. (2009). The role of the GPR91 ligand succinate in hematopoiesis. J Leukoc Biol 85: 837–843.
Halgren TA (1996). Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 17: 490–519.
He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J et al. (2004). Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429: 188–193.
Hogberg C, Gidlof O, Tan C, Svensson S, Nilsson-Ohman J, Erlinge D et al. (2011). Succinate independently stimulates full platelet activation via cAMP and phosphoinositide 3-kinase-beta signaling. J Thromb Haemost 9: 361–372.
Inoue A, Ishiguro J, Kitamura H, Arima N, Okutani M, Shuto A et al. (2012). TGFalpha shedding assay: an accurate and versatile method for detecting GPCR activation. Nat Methods 9: 1021–1029.
Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997). Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267: 727–748.
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010). Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160: 1577–1579.
Klenc J, Lipowska M, Taylor AT (2015). Identification of lead compounds for (99m)Tc and (18)F GPR91 radiotracers. Bioorg Med Chem Lett 25: 2335–2339.
Lee MH, Appleton KM, Strungs EG, Kwon JY, Morinelli TA, Peterson YK et al. (2016). The conformational signature of beta-arrestin2 predicts its trafficking and signalling functions. Nature 531: 665–668.
Lefkowitz RJ, Shenoy SK (2005). Transduction of receptor signals by beta-arrestins. Science 308: 512–517.
Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J, Zhang J et al. (2016). GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med 213: 1655–1662.
McCreath KJ, Espada S, Galvez BG, Benito M, de Molina A, Sepulveda P et al. (2015). Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity. Diabetes 64: 1154–1167.
McGrath JC, Lilley E (2015). Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol 172: 3189–3193.
Nuber S, Zabel U, Lorenz K, Nuber A, Milligan G, Tobin AB et al. (2016). beta-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531: 661–664.
Overington JP, Al-Lazikani B, Hopkins AL (2006). How many drug targets are there? Nat Rev Drug Discov 5: 993–996.
Peti-Peterdi J, Gevorgyan H, Lam L, Riquier-Brison A (2013). Metabolic control of renin secretion. Pflugers Arch 465: 53–58.
Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS et al. (2011). Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature 469: 175–180.
Robben JH, Fenton RA, Vargas SL, Schweer H, Peti-Peterdi J, Deen PM et al. (2009). Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int 76: 1258–1267.
Roth BL, Kroeze WK (2015). Integrated approaches for genome-wide interrogation of the druggable non-olfactory G protein-coupled receptor superfamily. J Biol Chem 290: 19471–19477.
Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N et al. (2008). Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 9: 1261–1269.
Sadagopan N, Li W, Roberds SL, Major T, Preston GM, Yu Y et al. (2007). Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens 20: 1209–1215.
Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH et al. (2008). The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 14: 1067–1076.
Shi J, Blundell TL, Mizuguchi K (2001). FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties. J Mol Biol 310: 243–257.
Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SPH et al. (2016). The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 44 (Database Issue): D1054-1068.
Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A et al. (2013). Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen 18: 599–609.
Spath B, Hansen A, Bokemeyer C, Langer F (2012). Platelet inhibition by acetylsalicylic acid and P2Y receptor antagonists. Platelets 23: 60–68.
Sundström L, Greasley PJ, Engberg S, Wallander M, Ryberg E (2013). Succinate receptor GPR91, a Gαi coupled receptor that increases intracellular calcium concentrations through PLCβ. FEBS Lett 587: 2399–2404.
Toma I, Kang JJ, Sipos A, Vargas S, Bansal E, Hanner F et al. (2008). Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest 118: 2526–2534.
Vargas SL, Toma I, Kang JJ, Meer EJ, Peti-Peterdi J (2009). Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J Am Soc Nephrol 20: 1002–1011.
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG et al. (2001). The sequence of the human genome. Science 291: 1304–1351.
Wettschureck N, Offermanns S (2005). Mammalian G proteins and their cell type specific functions. Physiol Rev 85: 1159–1204.
Wittenberger T, Schaller HC, Hellebrand S (2001). An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J Mol Biol 307: 799–813.
Zurwerra D, Glaus F, Betschart L, Schuster J, Gertsch J, Ganci W et al. (2012). Total synthesis of (−)-zampanolide and structure–activity relationship studies on (−)-dactylolide derivatives. Chemistry 18: 16868–16883.
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.