Succinate receptor 1 (SUCNR1), previously named G protein-coupled receptor 91 (GPR91), is a receptor that is activated by succinate, i.e., the anionic form of the dicarboxylic acid, succinic acid. 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. 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. 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, including roles in coordinating metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.. The succinyl CoA in this cycle may release its bound succinate; succinate is one of these mitochondrial-formed bioactive metabolites. SUCNR1 is a G protein-coupled receptor (GPR). 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. 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). 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. Cells exposed to a potentially tissue-damaging condition (e.g., severe inflammation, low energy levels due to excessive physical activity, or ischemia, i.e., shortage of the oxygen needed for cellular metabolism) 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. 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. 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. 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.
Cells and tissues expressing SUCNR1 SUCNR1 is expressed by human: a) hepatic stellate cells (i.e., pericytes found in the perisinusoidal space of the liver); b) neutrophils, macrophages, blood monocytes, monocyte-derived dendritic cells, CD34+ progenitor cells (i.e., bone marrow hematopoietic stem cells used therapeutically to restore hematopoiesis), blood platelets, megakaryocytes (i.e., platelet-producing cells), erythroblasts (i.e., red blood cell precursors), and the erythroleukemia cell line, TF-1; c) adipocytes (i.e., fat cells); d) endothelial cells in the veins and arteries of the placenta and umbilical cord; e) human umbilical vein endothelial cells; f) epithelial cells, fibroblasts, and certain cells in the lamina propria of the small and large intestines; g) mast cells; h) HK-2 cells (a kidney proximal tubule epithelial non-cancerous cell line); i) A549 lung, PC3 prostate, and HT-29 colin cancer cell lines; j) a subset (10%) of nasal solitary chemosensory cells; and k) cells in the retina, particularly retinal pigment epithelium cells.
SUCNR1 activators and inhibitors Succinate appears to be the primary agent that fully activates human SUCNR1. None of 800 tested compounds and 200 tested carboxylic acids fully activated SUCNR1 except for a) oxaloacetate, malate, α-ketoglutarate (α-ketoglutarate also activates the OXGR1 GPR receptor), and methylmalonate but were 5- to 10-fold less potent than succinate in doing so and b) two compounds/chemicals, cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid, which were respectively similar to and 10- to 20-fold more potent than succinate in activating SUCNR1. Agents that have been found to inhibit SUCNCR1 activation include NF-56-EJ40, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, and three compounds identified as 2c, 4c, and 5g. 4'-O-methylbavachadone, an active ingredient of the Chinese herbal remedy fructus psoraleae, has been reported to inhibit the binding of succinate to SUCNR1.
Functions regulated by SUCNR1
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