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succinate receptor

Family: Succinate receptor

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Gene Expression and Pathophysiology
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 330 3q24-3q25.1 SUCNR1 succinate receptor 1 18
Mouse 7 317 3 D Sucnr1 succinate receptor 1
Rat 7 317 2q31 Sucnr1 succinate receptor 1
Previous and Unofficial Names
succinate receptor 1
GPR91
G-protein coupled receptor 91
SUCNR1
P2Y purinoceptor 1-like
P2Y purinoceptor 1
G protein-coupled receptor 91
G-protein-coupled receptor 91
Database Links
DrugBank Target 4007 (Hs)
Ensembl ENSG00000198829 (Hs), ENSMUSG00000027762 (Mm), ENSRNOG00000014039 (Rn)
Entrez Gene 56670 (Hs), 84112 (Mm), 408199 (Rn)
GeneCards SUCNR1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Sucnr1 (Mm)
HomoloGene 41865 (Hs)
Human Protein Reference Database 16211 (Hs)
InterPro Q9BXA5 (Hs), Q99MT6 (Mm), Q6IYF9 (Rn)
KEGG Gene hsa:56670 (Hs), mmu:84112 (Mm), rno:408199 (Rn)
OMIM 606381 (Hs)
PharmGKB Gene PA28934 (Hs)
PhosphoSitePlus Q9BXA5 (Hs), Q99MT6 (Mm), Q6IYF9 (Rn)
Protein Ontology (PRO) PRO:000001556 (Hs)
RefSeq Nucleotide NM_033050 (Hs), NM_032400 (Mm), NM_001001518 (Rn)
RefSeq Protein NP_149039 (Hs), NP_115776 (Mm), NP_001001518 (Rn)
TreeFam ENSG00000198829 (Hs), ENSMUSG00000027762 (Mm), ENSRNOG00000014039 (Rn)
UniGene Hs. 279575 (Hs)
UniProt Q9BXA5 (Hs), Q99MT6 (Mm), Q6IYF9 (Rn)
Wikipedia succinate receptor
Succinate receptor
Search for 3D structures on the PDB
Search by keyword: Succinate receptor succinate receptor Search by accession number: Q6IYF9, Q9BXA5, Q99MT6
Natural/Endogenous Ligand(s)
succinic acid
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
succinic acid Hs Full agonist 4.04 – 4.7 pEC50 8
Agonist Comments
Using molecular docking calculations, it is predicted that SUCNR1 may interact with gamma-hydroxybutyrate [12].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
N-[{3-(3-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl}methyl]-4-([1,8]naphthyridin-2-yl)butyramide Hs Antagonist 7.46 pIC50 3
N-[{3-(3-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl}methyl]-4-([1,8]naphthyridin-2-yl)butyramide Rn Antagonist 6.87 pIC50 3
2-{4-[5-(3-Chloro-4-trifluoromethoxyphenyl)-[1,3,4]oxadiazol-2-yl]butyl}-[1,8]naphthyridine Hs Antagonist 6.74 pIC50 3
View species-specific antagonist tables
Antagonist Comments
There are several synthetic antagonists against SUCNR1 discovered from a systematic structure-activity relationship study [3]. Among these antagonists, N-[{3-(3-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl}methyl]-4-([1,8]naphthyridin-2-yl)butyramide (5g) and 2-{4-[5-(3-Chloro-4-trifluoromethoxyphenyl)-[1,3,4]oxadiazol-2-yl]butyl}-[1,8]naphthyridine (7e) are identified to have high pharmaceutical and clinical importance. 5g demonstrated satisfactory oral bioavailability in rats (%F: 26), very good plasma concentration (Cmax: 37uM, AUC0-24h: 69uM at 30mg/kg p.o. dose) and low plasma clearance. Similarly, 7e demonstrates low plasma clearance (2.0mL/min/kg), excellent bioavailability (%F: 87) and drug exposure (Cmax: 72uM, AUC0-24h: 471uMh, t1/2: 3.4h) upon oral admistration (30mg/kg p.o.) in rats.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Adenylate cyclase inhibition
Phospholipase C stimulation
Comments:  The findings by Correa et al. suggest that SUCNR1 does not activate G proteins in stellate cells [5].
References:  8,10-11
Tissue Distribution
Megakaryocytes, platelets, monocytes
Species:  Human
Technique:  RT-PCR
References:  11
CD34+ haematopoietic stem cells, megakaryocytes, erythroid progenitor cultures, bone marrow-derived stromal cell cultures.
Species:  Human
Technique:  RT-PCR and immunoblot
References:  7
Present in platelets, T cells, B cells and monocytes. Absent in granulocytes.
Species:  Human
Technique:  Western blot
References:  11
Kidney
Species:  Human
Technique:  Northen blot
References:  18
Platelets
Species:  Human
Technique:  RT-PCR, western blot and confocal immunofluorescene microscopy
References:  1
Immature monocyte-derived DCs (MoDCs), macrophages, T cells, B cells
Species:  Human
Technique:  RT-PCR
References:  14
Kidney and glomerular endothelial cells. No transcripts of SUCNR1 were detected in vascular smooth muscle cell and juxtaglomerular cell.
Species:  Mouse
Technique:  RT-PCR
References:  16
Kidney, liver
Species:  Mouse
Technique:  Northen blot
References:  18
Apical membrane of retinal pigment epithelium
Species:  Mouse
Technique:  in situ hybridisation
References:  6
Isolated adipocytes, white adipose tissues, kidney, liver, gall bladder, vena cava, skin, spleen, thyroid
Species:  Mouse
Technique:  RT-PCR
References:  13
Cortical region of mouse kidney, including proximal tubules, distal tubules, juxtaglomerular apparatus
Species:  Mouse
Technique:  in situ hybridisation
References:  8
Kidney, liver, spleen
Species:  Mouse
Technique:  RT-PCR
References:  7-8
Quiescent hepatic stellate cells. The transcipts of SUCNR1 were not detected in hepatocytes, cholangiocytes, Kuppffer cells, sinusoidal endothelial cells and portal fibroblasts
Species:  Rat
Technique:  RT-PCR and confocal immunofluorescence
References:  5
Ventricular cardiomyocytes
Species:  Rat
Technique:  RT-PCR, western blot and confocal microscopy
References:  1
Vascular endothelial cells in the afferent arteriole and glomerulus. No expression of SUCR1 was detected in juxtaglomerular cell.
Species:  Rat
Technique:  Immunohistochemistry
References:  16-17
Cell bodies of retinal ganglion cell layer and cells of the inner nuclear layer and outer retina
Species:  Rat
Technique:  Immunohistochemistry
References:  6
Apical membrane of macula densa cells
Species:  Rat
Technique:  Immunohistochemistry
References:  17
Tissue Distribution Comments
No transcripts of SUCNR1 were detected in the brain when examined by Northern blot analysis [4]. SUCNR1 is functionally expressed by immature dendritic cells after differentiation from monocytes and was rapidly downregulated after dendritic cell maturation [14]. SUCNR1 expression is enriched in both early and late-stage haematopoietic progenitor cells [7].
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Physiological Functions
Mediates hypertensive effect of succinate through the release of renin from the kidney and activation of the renin-angiotensin system.
Species:  Mouse
Tissue:  Kidney
References:  8-9
Mediates extracellular succinate-induced inhibition of lipolysis in white adipose tissue.
Species:  Mouse
Tissue:  White adipose tissue
References:  13
Mediates succinate-induced platelet aggregation of human platelets by decreasing cAMP levels and activating P13K [B]/Akt pathway, leading to P-selectin and glycoprotein IIb-IIIa activation.
Species:  Human
Tissue:  Platelets
References:  10
Mediates succinate-modulated Ca2+ transient in cardiomyocytes.
Species:  Rat
Tissue:  Cardiomyocytes
References:  1
Mediates the immunomodulatory effect of succinate, such as enhancing the secretion of proinflammatory cytokines by dendritic cells, inducing chemotaxis of dendritic cells, potentiating T cell activation and enhancing the homing of dendritic cells to draining lymph nodes.
Species:  Mouse
Tissue:  Dendritic cells
References:  14
Mediates the proliferation of TF-1 cell in response to succinate through Gi pathway activation of Erk1/2. Protect TF-1 cells from apoptosis induced by serum deprivation.
Species:  Human
Tissue:  Human erythroleukemic cell line
References:  8
Stimulate blood cell development in vivo under conditions of myelosuppression.
Species:  Mouse
Tissue:  Erythrocytes, platelets, neutrophils, lymphocytes
References:  8
Involved in the activation of MAPKs, COX-2 and the release of prostaglandin E2in macula densa cells, leading to renin release and renal angiotensin system activation.
Species:  Mouse
Tissue:  Macula densa
References:  17
Involved in retinal angiogenesis by regulating various angiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietins.
Species:  Rat
Tissue:  Retina ganglion cells
References:  15
Mediates the succinate-induced expression of VEGF in iron-overloaded retinal pigment epithelium cells.
Species:  Mouse
Tissue:  Retical pigment epithelium
References:  6
Physiological Functions Comments
SUCNR1 signaling may have a role in activating hepatic stellate cells to restore damaged tissue in the ischemic liver [2].
Physiological Consequences of Altering Gene Expression
Hypertension can not be induced by succinate in mice with SUCNR1 knockout.
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockouts
References:  8
The effect of succinate on Ca2+ transient in cardiomycytes is abolished in mice with SUCNR1 knockdown.
Species:  Rat
Tissue:  Cardiomyocytes
Technique:  RNA interference
References:  1
High glucose level-induced renin release is abolished in GPR91-/- mice.
Species:  Mouse
Tissue:  Kidney
Technique:  Breeding of GPR+/- mice
References:  16
Impaired migration of dendritic cells, diminished succinate-mediated immune responses, decreased T cell proliferation, weaker allograft rejection. SUCNR mice have impaired dendritic cell migration and diminished succinate-mediated immune responses such as chemotaxis of immature monocytes-driven dendritic cells and production of inflammotory cytokines. SUCNR-/- lymph node cells show lower ex vivo T cell proliferation. In addition, SUCNR-/- skin grafts show weaker allograft rejection responses than wild-type grafts.
Species:  Mouse
Tissue:  Embryonic stem cells
Technique:  Gene knockouts
References:  14
TF-1 cells with SUCNR1 knockdown do not proliferate in response to succinate.
Species:  Human
Tissue:  Human erythroleukemic cell line
Technique:  RNA interference
References:  7
Less tuft formation, extra-retinal neovascularization and blood vessel tortuosity. Rats with SUCNR1 knockdown are protected from retinal neovascularization in ischemic proliferative retinopathy.
Species:  Rat
Tissue:  Retina
Technique:  RNA interference
References:  15
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0002376 abnormal dendritic cell physiology PMID: 18820681 
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0008686 abnormal interleukin-2 secretion PMID: 18820681 
Sucnr1tm1Lex Sucnr1tm1Lex/Sucnr1tm1Lex
involves: 129S/SvEvBrd		 MGI:1934135  MP:0002136 abnormal kidney physiology PMID: 18535668 
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0005362 abnormal Langerhans cell physiology PMID: 18820681 
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0001828 abnormal T cell activation PMID: 18820681 
Sucnr1tm1Lex Sucnr1tm1Lex/Sucnr1tm1Lex
involves: 129S/SvEvBrd		 MGI:1934135  MP:0003353 decreased circulating renin level PMID: 18535668 
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0005095 decreased T cell proliferation PMID: 18820681 
Sucnr1tm1Dgen Sucnr1tm1Dgen/Sucnr1tm1Dgen
B6.129P2-Sucnr1		 MGI:1934135  MP:0004751 increased length of allograft survival PMID: 18820681 
Gene Expression and Pathophysiology Comments
The signalling of SUCNR1 is involved in various pathologies, such as renal hypertension, diabetic nephropathy, retinal angiogenesis, diabetic retinopathy and aggregation of platelets [2-3]. SUCNR1 signalling may also contribue to the formation of fibrosis [2].
General Comments
SUCNR1 is a plasma membrane receptor that responds to extracellular succinate [2] SUCRN1 is a novel potential drug target to prevent renal complications of diabetes [16]. The expression of SUCNR1 in retinal pigment epithelium cells is iron-dependent [6].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR91 (SUCNR1) (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0331C2A
DiscoveRx PathHunter® eXpress GPR91 CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0331E2ACP1

REFERENCES

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1. Aguiar, CJ; Andrade, VL; Gomes, ER; Alves, MN; Ladeira, MS; Pinheiro, AC; Gomes, DA; Almeida, AP; Goes, AM; Resende, RR; et al.. (2010) Succinate modulates Ca(2+) transient and cardiomyocyte viability through PKA-dependent pathway. Cell Calcium, 47 (1): 37-46. [PMID:20018372]

2. Ariza, AC; Deen, PM; Robben, JH. (2012) The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. Front Endocrinol (Lausanne), 3: 22. [PMID:22649411]

3. Bhuniya, D; Umrani, D; Dave, B; Salunke, D; Kukreja, G; Gundu, J; Naykodi, M; Shaikh, NS; Shitole, P; Kurhade, S; et al.. (2011) Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg. Med. Chem. Lett., 21 (12): 3596-602. [PMID:21571530]

4. Cantagrel, V; Lossi, AM; Boulanger, S; Depetris, D; Mattei, MG; Gecz, J; Schwartz, CE; Van Maldergem, L; Villard, L. (2004) Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males. J. Med. Genet., 41 (10): 736-42. [PMID:15466006]

5. Correa, PR; Kruglov, EA; Thompson, M; Leite, MF; Dranoff, JA; Nathanson, MH. (2007) Succinate is a paracrine signal for liver damage. J. Hepatol., 47 (2): 262-9. [PMID:17451837]

6. Gnana-Prakasam, JP; Ananth, S; Prasad, PD; Zhang, M; Atherton, SS; Martin, PM; Smith, SB; Ganapathy, V. (2011) Expression and iron-dependent regulation of succinate receptor GPR91 in retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci., 52 (6): 3751-8. [PMID:21357408]

7. Hakak, Y; Lehmann-Bruinsma, K; Phillips, S; Le, T; Liaw, C; Connolly, DT; Behan, DP. (2009) The role of the GPR91 ligand succinate in hematopoiesis. J. Leukoc. Biol., 85 (5): 837-43. [PMID:19204147]

8. He, W., Miao, F. J., Lin, D. C., Schwandner, R. T., Wang, Z., Gao, J., Chen, J. L., Tian, H. and Ling, L. (2004) Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature, 429: 188-193. [PMID:15141213]

9. Hebert, SC. (2004) Physiology: orphan detectors of metabolism. Nature, 429 (6988): 143-5. [PMID:15141197]

10. Högberg, C; Gidlöf, O; Tan, C; Svensson, S; Nilsson-Öhman, J; Erlinge, D; Olde, B. (2011) Succinate independently stimulates full platelet activation via cAMP and phosphoinositide 3-kinase-β signaling. J. Thromb. Haemost., 9 (2): 361-72. [PMID:21143371]

11. Macaulay, IC; Tijssen, MR; Thijssen-Timmer, DC; Gusnanto, A; Steward, M; Burns, P; Langford, CF; Ellis, PD; Dudbridge, F; Zwaginga, JJ; Watkins, NA; van der Schoot, CE; Ouwehand, WH. (2007) Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood, 109 (8): 3260-9. [PMID:17192395]

12. Molnár, T; Héja, L; Emri, Z; Simon, A; Nyitrai, G; Pál, I; Kardos, J. (2011) Activation of astroglial calcium signaling by endogenous metabolites succinate and gamma-hydroxybutyrate in the nucleus accumbens. Front Neuroenergetics, 3: 7. [PMID:22180742]

13. Regard, J.B., Sato, I.T. and Coughlin, S.R. (2008) Anatomical profiling of G protein-coupled receptor expression. Cell, 135: 561-571. [PMID:18984166]

14. Rubic, T; Lametschwandtner, G; Jost, S; Hinteregger, S; Kund, J; Carballido-Perrig, N; Schwärzler, C; Junt, T; Voshol, H; Meingassner, JG; et al.. (2008) Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol., 9 (11): 1261-9. [PMID:18820681]

15. Sapieha, P; Sirinyan, M; Hamel, D; Zaniolo, K; Joyal, JS; Cho, JH; Honoré, JC; Kermorvant-Duchemin, E; Varma, DR; Tremblay, S; et al.. (2008) The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat. Med., 14 (10): 1067-76. [PMID:18836459]

16. Toma, I; Kang, JJ; Sipos, A; Vargas, S; Bansal, E; Hanner, F; Meer, E; Peti-Peterdi, J. (2008) Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J. Clin. Invest., 118 (7): 2526-34. [PMID:18535668]

17. 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 (5): 1002-11. [PMID:19389848]

18. 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 (3): 799-813. [PMID:11273702]

To cite this database page, please use the following:

Wen Chiy Liew.
Succinate receptor: succinate receptor. Last modified on 08/02/2013. Accessed on 19/06/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=166.


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