Succinate receptor: Introduction

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The Succinate receptor was first identified in a megacaryocytic cell line in 1995 and called "P2U2", a name coined for its homology with the purinergic receptor P2Y2, known as P2U at that time [5]. The SUCNR1 gene was later re-discovered as GPR91 in 2001 on human chromosome 3q24-3q25 using an expressed sequence tag data mining strategy [8]. There is a high degree of homology between human and mouse (68%) with the exception of the C-terminal tail, which is 12 AA shorter in rodents [2,8]. In humans, other genes have been found on the same locus and consist in a cluster of P2Y1, P2Y12, P2Y13, H963 (GPR171) and GPR87 [1]. In their seminal paper, Wittenberger et al. speculated that all these receptors originated from a common ancestor, presumably a nucleotide receptor [8]. Although the Succinate receptor was initially viewed as a purinergic receptor and predicted to bind purinergic ligands [3,7], it has been paired by He et al. with a molecule not even remotely similar to purines: succinate [6].

Receptors responding to purines and their derivatives are classified between ionic channels P2X and metabotropic receptors (GPCRs) P2Y. In 2006, the P2Y family was divided between P2Y1-like receptors and P2Y12-like receptors based on three criteria [1]. First, phylogenetic similarity, second the presence of AA motifs proposed to be important for ligand binding, and, third, primary G-protein coupling. Regarding the second criterion, SUCNR1 has some interesting similarities with P2Y1-like receptors in the TM6 such as the H6.52XXR/K6.55 and a slightly modified Q/KXXR (SUCNR1 has IVTR7.38) motifs. They might be important for agonist activity. For the third criterion, SUCNR1, just like P2Y12, 13, 14 receptors, almost exclusively couples to Gi/o (see below) in contrast with P2Y1-like receptors that preferentially activate Gq signalling and induce calcium release [1]. Therefore, with regard to purinergic receptor classification, the Succinate Receptor cannot be related to either class, although it has striking similarities with this family.

Although SUCNR1 has not been crystallized yet, the information on its structure can be hypothesized by comparison with closely related proteins. Two representative purinergic receptors (P2Y1 and P2Y12) have been crystallized so far [9-11] and some careful inferences can be made on SUCNR1 structure. Most notably, homology models and targeted mutagenesis have provided some information on the binding pocket. Four amino acids seem to be involved in succinate binding, namely R993.29, R2817.39, R2526.55 and H1033.33 [6]. Succinate negative charges adopt a cis conformation when bound to the receptor and interact directly with positively charged R2817.39 and R2526.55 [4]. Accordingly, fumarate, which has a trans conformation does not bind to the Succinate receptor [4,6]. Three criteria have been proposed for agonist activity at the receptor: 1) two negative charges, 2) a cis conformation and 3) a distance of 3 to 4 carbon atoms between these charges [4].

References

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1. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA et al.. (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol. Rev.58 (3): 281-341. [PMID:16968944]

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. Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol63: 1256-1272. [PMID:12761335]

4. Geubelle P, Gilissen J, Dilly S, Poma L, Dupuis N, Laschet C, Abboud D, Inoue A, Jouret F, Pirotte B et al.. (2017) Identification and pharmacological characterization of succinate receptor agonists. Br. J. Pharmacol.174 (9): 796-808. [PMID:28160606]

5. Gonzalez NS, Communi D, Hannedouche S, Boeynaems JM. (2004) The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids. Purinergic Signal.1 (1): 17-20. [PMID:18404396]

6. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L. (2004) Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature429: 188-193. [PMID:15141213]

7. Joost P, Methner A. (2002) Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biol.3 (11): RESEARCH0063. [PMID:12429062]

8. 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]

9. Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W et al.. (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature520 (7547): 317-21. [PMID:25822790]

10. Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Müller CE et al.. (2014) Agonist-bound structure of the human P2Y12 receptor. Nature509 (7498): 119-22. [PMID:24784220]

11. Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W et al.. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature,  [Epub ahead of print]. [PMID:24670650]

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To cite this family introduction, please use the following:

Julien Hanson.
Succinate receptor, introduction. Last modified on 10/08/2017. Accessed on 24/09/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=446.