Succinate receptor 1 (SUCNR1), previously named G protein-coupled receptor 91 (GPR91),[5] is a receptor that is activated by succinate, i.e., the anionic form of the dicarboxylic acid, succinic acid.[6] Succinate and succinic acid readily convert into each other by gaining (succinate) or losing (succinic acid) protons, i.e., H+ (see Ions). Succinate is by far the predominant form of this interconversion in living organisms.[7] Succinate is one of the intermediate metabolites in the citric acid cycle (also termed the TCA cycle or tricarboxylic acid cycle). This cycle is a metabolic pathway that operates in the mitochondria of virtually all eucaryotic cells. It consists of a series of biochemical reactions that serve the vital function of releasing the energy stored in nutrient carbohydrates, fats, and proteins.[8] Recent studies have found that some of the metabolites in this cycle are able to regulate various physiological and pathological functions in a wide range of cell types. The succinyl CoA in this cycle may release its bound succinate; succinate is one of these mitochondrial-formed bioactive metabolites.[6][8][9]
SUCNR1 is a G protein-coupled receptor (GPR).[10] GPRs are cell surface receptors that bind any one of a specific set of ligands which they recognize and thereby are activated to elicit certain types of responses in their parent cells.[10][11] The human SUCNR1 protein is encoded (i.e. its synthesis is directed) by the SUCNR1 gene. This gene is located at band position 25.1 on the long (i.e., "q") arm of human chromosome 3 (gene location notated as 3q25.1).[12][13] Most studies have reported that the SUCNR1 protein consists of 330 amino acids although a few studies have detected a 334 amino acid product of this gene.[13]
Cells exposed to a potentially tissue-damaging condition (e.g., severe inflammation, low energy levels due to excessive physical activity,[14] or ischemia, i.e., shortage of the oxygen needed for cellular metabolism[7]) develop rising levels of succinate in their mitochondrial matrix. The excess mitochondrial succinate flows into the cells' cytoplasm, adjacent extracellular matrix, and circulatory system. In addition, the succinate in food as well as that released by certain microorganisms and helminths (i.e., parasitic worms) in the gastrointestinal tract are absorbed into the walls of the small and large intestines.[9][15] The succinate released by cells works as a signaling molecule to stimulate diverse functions in cells near or, after entering the circulation, far from the cells of origin while the intestinal succinate may stimulate cells in the intestines' walls. The stimulating actions of succinate often involve the activation of the SUCNR1 on cells.[6][8] However, succinate can also alter cell functions by succinylating (i.e., covalently binding as a succinyl group to) lysine amino acid residues in various proteins, by stabilizing the transcription factor HIF1A, by stimulating the production of reactive oxygen species, or by altering the expression of various genes (see Biological functions of succinate). Consequently, studies implicating SUCNR1 in the actions of succinate should show that its actions are suppressed by reducing the expression of SUCNR1, by blocking succinate's binding to SUCNR1. or by inhibiting the activity of SUCNR1.[9][16]
The research conducted to date on the function of SUCNR1 has been mostly preclinical studies in animals. These studies have shown that the activation of SUCNR1 by succinate produces a wide range of beneficial or detrimental effects on: the breakdown of fat tissue triglycerides; obesity; fatty acid levels in the liver; certain fatty acid liver diseases; blood glucose levels; diabetes; and certain heart, kidney, eye, vascular, and inflammatory diseases; and certain cancers. Consequently, the use of methods that stimulate or inhibit SUCNR1 to treat these diseases runs the risk of producing very undesirable side effects. Studies are needed to better define the beneficial versus detrimental effects of these treatments in mice and carry the studies to humans in order to determine if blocking or promoting SUCNR1's actions can be used as a safe treatment strategy.[15][17][18]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000198829 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027762 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Detraux D, Renard P (July 2022). "Succinate as a New Actor in Pluripotency and Early Development?". Metabolites. 12 (7): 651. doi:10.3390/metabo12070651. PMC 9325148. PMID 35888775.
- ^ a b c Mills EL, Harmon C, Jedrychowski MP, Xiao H, Garrity R, Tran NV, Bradshaw GA, Fu A, Szpyt J, Reddy A, Prendeville H, Danial NN, Gygi SP, Lynch L, Chouchani ET (May 2021). "UCP1 governs liver extracellular succinate and inflammatory pathogenesis". Nature Metabolism. 3 (5): 604–617. doi:10.1038/s42255-021-00389-5. PMC 8207988. PMID 34002097.
- ^ a b Tretter L, Patocs A, Chinopoulos C (August 2016). "Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1857 (8): 1086–1101. doi:10.1016/j.bbabio.2016.03.012. PMID 26971832.
- ^ a b c Arnold PK, Finley LW (February 2023). "Regulation and function of the mammalian tricarboxylic acid cycle". The Journal of Biological Chemistry. 299 (2): 102838. doi:10.1016/j.jbc.2022.102838. PMC 9871338. PMID 36581208.
- ^ a b c Fernández-Veledo S, Ceperuelo-Mallafré V, Vendrell J (September 2021). "Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis". Trends in Endocrinology and Metabolism. 32 (9): 680–692. doi:10.1016/j.tem.2021.06.003. PMID 34301438. S2CID 236097682.
- ^ a b Liang C, Li J, Tian B, Tian L, Liu Y, Li J, Xin L, Wang J, Fu C, Shi Z, Xia J, Liang Y, Wang K (December 2021). "Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment". Biomedicine & Pharmacotherapy. 144: 112298. doi:10.1016/j.biopha.2021.112298. PMID 34649219. S2CID 238990829.
- ^ Weis WI, Kobilka BK (June 2018). "The Molecular Basis of G Protein-Coupled Receptor Activation". Annual Review of Biochemistry. 87: 897–919. doi:10.1146/annurev-biochem-060614-033910. PMC 6535337. PMID 29925258.
- ^ "Entrez Gene: SUCNR1 succinate receptor 1".
- ^ a b Gilissen J, Jouret F, Pirotte B, Hanson J (March 2016). "Insight into SUCNR1 (GPR91) structure and function" (PDF). Pharmacology & Therapeutics. 159: 56–65. doi:10.1016/j.pharmthera.2016.01.008. hdl:2268/194560. PMID 26808164. S2CID 24982373.
- ^ Suresh MV, Aktay S, Yalamanchili G, Solanki S, Sathyarajan DT, Arnipalli MS, Pennathur S, Raghavendran K (September 2023). "Role of succinate in airway epithelial cell regulation following traumatic lung injury". JCI Insight. 8 (18). doi:10.1172/jci.insight.166860. PMC 10561732. PMID 37737265.
- ^ a b Wu KK (July 2023). "Extracellular Succinate: A Physiological Messenger and a Pathological Trigger". International Journal of Molecular Sciences. 24 (13): 11165. doi:10.3390/ijms241311165. PMC 10342291. PMID 37446354.
- ^ Krzak G, Willis CM, Smith JA, Pluchino S, Peruzzotti-Jametti L (January 2021). "Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation". Trends in Immunology. 42 (1): 45–58. doi:10.1016/j.it.2020.11.004. PMID 33279412. S2CID 227522279.
- ^ Kuo CC, Wu JY, Wu KK (November 2022). "Cancer-derived extracellular succinate: a driver of cancer metastasis". Journal of Biomedical Science. 29 (1): 93. doi:10.1186/s12929-022-00878-z. PMC 9641777. PMID 36344992.
- ^ Rubić-Schneider T, Carballido-Perrig N, Regairaz C, Raad L, Jost S, Rauld C, Christen B, Wieczorek G, Kreutzer R, Dawson J, Lametschwandner G, Littlewood-Evans A, Carballido JM (March 2017). "GPR91 deficiency exacerbates allergic contact dermatitis while reducing arthritic disease in mice". Allergy. 72 (3): 444–452. doi:10.1111/all.13005. PMC 5324651. PMID 27527650.