Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions

Favret, Sandra; Binet, Francois; Lapalme, Eric; Leboeuf, Dominique; Carbadillo, Jose; Rubic, Tina; Picard, Emilie; Mawambo, Gaelle; Tetreault, Nicolas; Joyal, Jean-Sébastien; Chemtob, Sylvain; Sennlaub, Florian; SanGiovanni, John Paul; Guimond, Martin; Sapieha, Przemyslaw

doi:10.18632/aging.100563

Cited by 26 publications

(31 citation statements)

References 37 publications

(31 reference statements)

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“…For example, succinate signaling via GPR91 is part of the cell’s hypoxia response that works in parallel with, but independently of, hypoxia-inducible factor (HIF) to activate classic hypoxia genes such as the gene encoding vascular endothelial growth factor (VEGF) (Figure 2) (18). However, GPR91 activation appears to be a double-edged sword because the dysfunction or overactivation of this pathway may lead to the development of various pathologies (18, 22, 27, 28). He et al (12), in their pioneering report, proposed that GPR91 plays an important role in the succinate-induced hypertensive effect and may be involved in renovascular hypertension, a disease linked to diabetes, renal failure, and atherosclerosis.…”

Section: Mitochondrial Citric Acid Cycle Intermediates and Their Gpcrsmentioning

confidence: 99%

“…Therefore, the mechanisms of GPR91 signaling in RGCs in the retina that promote angiogenesis, and those in MD cells in the JGA and kidney that cause renin release, are essentially identical. In addition to RGCs, another retinal cell type, the retinal pigment epithelium, also shows functional GPR91 expression; GPR91 plays a role in the maintenance of normal tissue cellular composition (27, 38). …”

Section: Mitochondrial Citric Acid Cycle Intermediates and Their Gpcrsmentioning

confidence: 99%

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Regulation of Vascular and Renal Function by Metabolite Receptors

Peti-Peterdi

Kishore

Pluznick

2016

Annu. Rev. Physiol.

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To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis—from salt and water balance to metabolism—by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families—(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and (c) short-chain fatty acid receptors—we emphasize the unique and important roles that these receptors play in renal and vascular physiology and pathophysiology.

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“…Besides RGC, SUCNR1 is also present in retinal pigment epithelium (RPE) (Favret et al, 2013;GnanaPrakasam et al, 2011). Accordingly, a role for the receptor present in these cells has been suggested in hemochromatosis.…”

Section: Retinal Angiogenesismentioning

confidence: 99%

Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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“…Excessive iron accumulation, ferric ammonium citrate supply and cytomegalovirus infection upregulate GPR91 [6] . Genetic analysis suggests that patients with an intron variant of GPR91 gene (SUCNR1) are at a higher risk for geographic atrophy, which is supported by the observation that GPR91-deficient mice have a variety of premature sub-retinal dystrophy, including abnormal thickening of Bruch’s membrane and a buildup of subretinal microglia [32] .…”

Section: Role Of Gpr91 In the Retinamentioning

confidence: 99%

G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases

et al. 2017

Vision Research

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G protein-coupled receptor 91 (GPR91) is a succinate-specific receptor and activation of GPR91 could initiate a complex signal transduction cascade and upregulate inflammatory and pro-angiogenic cytokines. In the retina, GPR91 is predominately expressed in ganglion cells, a major cellular entity involved in the pathogenesis of diabetic retinopathy (DR) and other hypoxic retinal diseases. During the development of DR and retinopathy of prematurity (ROP), chronic hypoxia causes an increase in the levels of local succinate. Succinate-mediated GPR91 activation upregulates vascular endothelial growth factor (VEGF) through ERK1/2-C/EBP β (c-Fos) and/or ERK1/2-COX-2/PGE2 signaling pathways, which in turn, leads to the breakdown of blood-retina barriers in these disorders. In this review, we will have a brief introduction of GPR91 and its biological functions and a more detailed discussion about the role and mechanisms of GPR91 in DR and ROP. A better understanding of GPR91 regulation may be of great significance in identifying new biomarkers and drug targets for the prediction and treatment of DR, ROP, and hypoxic retinal diseases.

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Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions

Cited by 26 publications

References 37 publications

Regulation of Vascular and Renal Function by Metabolite Receptors

Insight into SUCNR1 (GPR91) structure and function

G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases

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