Identification and pharmacological characterization of succinate receptor agonists

Geubelle, Pierre; Gilissen, Julie; Dilly, Sébastien; Poma, Laurence; Dupuis, Nadine; Laschet, Céline; Abboud, Dayana; Inoue, Asuka; Jouret, François; Pirotte, Bernard; Hanson, Julien

doi:10.1111/bph.13738

Cited by 52 publications

(47 citation statements)

References 45 publications

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“…We then challenged PRP with ADP together with succinate or any of two synthetic non‐metabolite agonists of GPR91, namely cES or Cmpd131. While cES is a conformationally constrained succinate analog, Cmpd131 is a larger backbone modified analog with an amide‐linked hydrophobic “side chain,” which fits into a side pocket of GPR91 . Succinate, the endogenous receptor ligand, and the two synthetic agonists all enhanced ADP‐induced platelet aggregation (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…While cES is a conformationally constrained succinate analog, Cmpd131 is a larger backbone modified analog with an amide-linked hydrophobic "side chain," which fits into a side pocket of GPR91. 17,18 Succinate, the endogenous receptor ligand, and the two synthetic agonists all enhanced ADP-induced platelet aggregation ( Figure 1). We also synthesized a potent and selective antagonist of GPR91, here denoted XT1, according to a previously published synthetic strategy (Compound 4c in 19 ).…”

Section: Gpr91 Signaling Enhances Adp-mediated Platelet Activation mentioning

confidence: 99%

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Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

Tang

Fuchs

Tan

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Succinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell types including platelets. Platelet‐derived eicosanoids play pivotal roles in platelet activation/aggregation, which is key to thrombus formation and progression of atherothrombosis. Objectives This study aims to decipher the molecular mechanism(s) and potential involvement of eicosanoids in succinate enhanced platelet activation/aggregation. Methods We used liquid chromatography‐mass spectrometry (LC‐MS)/MS‐based lipid mediator profiling to identify eicosanoids regulated by succinate. We ran light transmittance aggregometry and flow cytometry to assess platelet aggregation, P‐selectin expression, and platelet‐polymorphonuclear leukocyte (PMN) adherence. Various pharmacological tools were used to assess the contributions of GPR91 signalling and eicosanoids in platelet aggregation. Results Succinate and two types of synthetic non‐metabolite GPR91 agonists—cis‐epoxysuccinate (cES) and Cmpd131—potentiated platelet aggregation, which was partially blocked by a selective GPR91 antagonist XT1. GPR91 activation increased production of 12‐hydroxy‐eicosatetraenoic acid (12‐HETE), thromboxane (TX) A2, and 12‐hydroxy‐heptadecatrienoic acid (12‐HHT) in human platelets, associated with phosphorylation of cytosolic phospholipase A2 (cPLA2), suggesting increased availability of free arachidonic acid. Blocking 12‐HETE and TXA2 synthesis, or antagonism of the TXA2 receptor, significantly reduced platelet aggregation enhanced by GPR91 signalling. Moreover, platelet‐PMN suspensions challenged with succinate exhibited enhanced transcellular biosynthesis of leukotriene C4 (LTC4), a powerful proinflammatory vascular spasmogen. Conclusion Succinate signals through GPR91 to promote biosynthesis of eicosanoids, which contribute to platelet aggregation/activation and potentially vascular inflammation. Hence, GPR91 may be a suitable target for pharmacological intervention in atherothrombotic conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Gpr91 Signaling Enhances Adp-mediated Platelet Activation mentioning

confidence: 99%

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

Tang

Fuchs

Tan

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Solid line: direct reaction; dotted line: multiple reactions but also in other tissues and organs beyond the immune system. This is important because, as a GPCR, SUCNR1 is a highly druggable target accessible with available small molecules [36][37][38][39]. Accordingly, the physiological and pathological functions of extracellular succinate deserve further investigation to evaluate the potential of its receptor as a pharmacological target.…”

Section: Succinate a Metabolite With Pleiotropic Functionsmentioning

confidence: 99%

Gut microbiota-derived succinate: Friend or foe in human metabolic diseases?

Fernández‐Veledo

Vendrell

2019

Rev Endocr Metab Disord

188

147

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There is now a wealth of evidence showing that communication between microbiota and the host is critical to sustain the vital functions of the healthy host, and disruptions of this homeostatic coexistence are known to be associated with a range of diseases including obesity and type 2 diabetes. Microbiota-derived metabolites act both as nutrients and as messenger molecules and can signal to distant organs in the body to shape host pathophysiology. In this review, we provide a new perspective on succinate as a gut microbiota-derived metabolite with a key role governing intestinal homeostasis and energy metabolism. Thus, succinate is not merely a major intermediary of the TCA traditionally considered as an extracellular danger signal in the host, but also a byproduct of some bacteria and a primary cross-feeding metabolite between gut resident microbes. In addition to maintain a healthy microbiome, specific functions of microbiota-derived succinate in peripheral tissues regulating host nutrient metabolism should not be rule out. Indeed, recent research point to some probiotic interventions directed to modulate succinate levels in the intestinal lumen, as a new microbiota-based therapies to treat obesity and related co-morbidities. While further research is essential, a large body of evidence point to succinate as a new strategic mediator in the microbiota-host cross-talk, which might provide the basis for new therapeutically approaches in a near future.

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“…The increased expression of the succinate receptor in response to excessive iron could be one of the factors underlying the connection between iron overload and cancer. Recently pharmacological agonists have been identified (e.g., cis-epoxysuccinate) that activate the succinate receptor with potencies greater than that of succinate [94]. These new agonists represent useful experimental tools to investigate the function of the receptor and its relevance to cancer.…”

Section: Cell-surface Receptors For Lactate and Succinate And Theimentioning

confidence: 99%

“…GPR109A was first identified as the receptor for the B-complex vitamin niacin [94, 95]. Niacin has been in use for several decades as a lipid-lowering drug, reducing circulating levels of cholesterol, decreasing LDL and increasing HDL, but the molecular mechanism responsible for these pharmacological actions of niacin remained unknown.…”

Section: Gpr109a As the Receptor For Butyrate And β-Hydroxybutyratmentioning

confidence: 99%

Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer

Ristić

Bhutia

Ganapathy

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Mitochondria are the sites of pyruvate oxidation, citric acid cycle, oxidative phosphorylation, ketogenesis, and fatty acid oxidation. Attenuation of mitochondrial function is one of the most significant changes that occurs in tumor cells, directly linked to oncogenesis, angiogenesis, Warburg effect, and epigenetics. In particular, three mitochondrial enzymes are inactivated in cancer: pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and 3-hydroxy-3-methylglutaryl CoA synthase-2 (HMGCS2). These enzymes are subject to regulation via acetylation/deacetylation. SIRT3, the predominant mitochondrial deacetylase, directly targets these enzymes for deacetylation and maintains their optimal catalytic activity. SIRT3 is a tumor suppressor, and deacetylation of these enzymes contributes to its biological function. PDH catalyzes the oxidative decarboxylation of pyruvate into acetyl CoA, SDH oxidizes succinate into fumarate, and HMGCS2 controls the synthesis of the ketone body β-hydroxybutyrate. As the activities of these enzymes are decreased in cancer, tumor cells accumulate lactate and succinate but produce less amounts of β-hydroxybutyrate. Apart from their role in cellular energetics, these metabolites function as signaling molecules via specific cell-surface G-protein-coupled receptors. Lactate signals via GPR81, succinate via GPR91, and β-hydroxybutyrate via GPR109A. In addition, lactate activates hypoxia-inducible factor HIF1α and succinate promotes DNA methylation. GPR81 and GPR91 are tumor promoters, and increased production of lactate and succinate as their agonists drives tumorigenesis by enhancing signaling via these two receptors. In contrast, GPR109A is a tumor suppressor, and decreased synthesis of β-hydroxybutyrate as its agonist suppresses signaling via this receptor, thus attenuating the tumor-suppressing function of GPR109A. In parallel with the opposing changes in lactate/succinate and β-hydroxybutyrate levels, tumor cells upregulate GPR81 and GPR91 but downregulate GPR109A. As such, these three metabolite receptors play a critical role in cancer and represent a new class of drug targets with selective antagonists of GPR81 and GPR91 for cancer treatment and agonists of GPR109A for cancer prevention.

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Identification and pharmacological characterization of succinate receptor agonists

Abstract: We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.

Cited by 52 publications

References 45 publications

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

Gut microbiota-derived succinate: Friend or foe in human metabolic diseases?

Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer

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