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OXGR1, i.e., 2-oxoglutarate receptor 1 (also known as GPR99, cysteinyl leukotriene receptor E, i.e., CysLTE, and cysteinyl leukotriene receptor 3, i.e., CysLT3[1][2]) is a G protein-coupled receptor located on the surface membranes of certain cells. It functions by binding one of its ligands and thereby becoming active in triggering pre-programmed responses in its parent cells. OXGR1 has been shown to bind and become activated by α-ketoglutarate,[3] itaconate,[4] and three cysteiny-containing leukotrienes (abbreviated as CysLTs), leukotriene E4 (i.e., LTE4), LTC4, and LTD4.[1][5] α-Ketoglutarate and itaconate are the dianionic forms of α-ketoglutaric acid and itaconic acid, respectively. α-Ketoglutaric and itaconic acids are short-chain dicarboxylic acids containing two carboxyl groups (notated as -CO2H) both which are bound to hydrogen (i.e., H+). However, at the basic pH levels (i.e., pH>7) in virtually all animal tissues, α-ketoglutaric acid and itaconic acid exit almost exclusively as α-ketoglutarate and itaconate, i.e., with their carboxy residues being negatively charged (notated as -CO2, because they are not bound to H+. It is α-ketoglutarate and itaconate, not α-ketoglutaric or itaconic acids, that bind to and activate OXGR1.[3][4]

History[edit]

In 2001, a human gene projected to code for a G protein-coupled receptor (i.e., a receptor that stimulates cells by activating G proteins) was identified. Its protein product was classified as an orphan receptor, i.e., a receptor whose activating ligand and function were unknown. The projected amino acid sequence of the protein encoded by its gene bore similarities to the purinergic receptor, P2Y1, and therefore might, like P2Y1, be a receptor for purines. This study named the new receptor and its gene GPR80 and GPR80, respectively.[6] Shortly thereafter, a second study found this same gene, indicated that it coded for a G protein-coupled receptor, had an amino acid sequence similar to two purinergic receptors, P2Y1 and GPR91, and determined that a large series of purine nucleotides, other nucleotides, and derivatives of these compounds did not activate this receptor. The study named this receptor GPR99.[7] A third study published in 2004 reported an orphan G protein-coupled receptor with an amino acid sequence similar to the P2Y receptor family of nucleotides was activated by to two purines, adenosine and adenosine monophosphate. The study nominated this receptor to be a purinergic receptor and named it the P2Y15 receptor.[8] However, a review of these studies in the same year by members of the International Union of Pharmacology Subcommittee for P2Y Receptor Nomenclature and Classification decided that GPR80/GPR99 is not a receptor for adenosine, adenosine monophosphate, or any other nucleotide.[9] A fourth study, also published in 2004, found that GPR80/GPR99 -bearing cells responded to α-ketoglutarate.[10] In 2013, IUPHAR accepted this report and the names OXGR1 and OXGR1 for the α-ketoglutarate responsive receptor and its gene, respectively.[11]. In 2013, a fifth study found that LTE4, LTC4, and LTD4 bound to and activated OXGR1.[1] Finally, a 2023 study provided evidence that itaconate activated the OXGR1 receptor.[4]

OXGR1 gene[edit]

The human OXGR1 gene is located on chromosome 13 at position 13q32.2; that is, it resides at position 32.2 (i.e., region 3, band 2, sub-band 2) on the "q" arm (i.e., long arm) of chromosome 13.[7][12] OXGR1 codes for a G protein coupled-receptor that is primarily linked to and activates heterotrimeric G proteins containing the Gq alpha subunit. When bound to any of its ligands, OXGR1 activates Gq alpha subunit-regulated cellular pathways (see Function of the Gq alpha pathways) that stimulate the cellular responses they are programmed to issue.[13][14]

OXGR1 activating and inhibiting ligands[edit]

Activating ligands[edit]

OXGR1 is the receptor for α-ketoglutarate, LTE4, LTC4, LTD4, and itaconate. These ligands have the following relative potencies in stimulating responses in OXGR1-bearing cells that have been isolated :

LTE4 >> LTC4 = LTD4 > α-ketoglutarate = itaconate

LTE4 is able to stimulate responses in at least some of its target cells at concentrations as low as a few picomoles/liter[1][4] whereas LTC4, LTD4, α-ketoglutarate, and itaconate require far higher levels to do so.[15]

The relative potencies that LTC4, LTD4, and LTE4 have in activating their target CysLT receptors, i.e., Cysteinyl leukotriene receptor 1 (CysLTR1), and Cysteinyl leukotriene receptor 2, and OXGR1 are: [2]

CysLT1 receptor: LTD4 > LTC4 >> LTE4
CysLT2 receptor: LTC4 = LTD4 >> LTE4
OXGR1 receptor: LTE4 > LTC4 > LTD4

These relationships suggest that CysTR1 and CysLTR2 are physiological receptors for LTD4 and LTC4 but perhaps not for LTE4. Indeed, the LTE4 concentrations required to activate LTD4 and LTC4 may be higher than those that develop in vivo (see Functions of OXGR1 in mediating the actions of LTE4, LTD4, and LTC4). These potency considerations suggest that the actions of LTE4 are mediated, at least to a large extent, by OXGR1. Several findings support this notion: a) pretreatment of guinea pig trachea and human bronchial smooth muscle with LTE4 but not LTC4 or LTD4 enhances their contraction responses to histamine; b) LTE4 is as potent as LTC4 and LTD4 in eliciting vascular leakage when injected into the skin of guinea pigs and humans; c) inhalation of LTE4 but not LTD4 by asthmatic subjects caused the accumulation of eosinophils and basophils in their bronchial mucosa; d) mice engineered to lack Cysltr1 and Cysltr2 receptors exhibited edema responses to the intradermal injection of LTC4, LTD4, and LTE4 but LTE4 was more potent (by a factor of 64-fold) in these responses in these mice compared to that in wild type mice; and e) mice engineered to lack all three Cysltr1, Cysltr2, and OXGR1 receptors showed no dermal edema responses to the injection of LTC4, LTD4, or LTE4.[1][5]

Inhibiting ligand[edit]

OXGR1 is inhibited by Montelukast, a well-known and clinically useful receptor antagonist, i.e., receptor activation inhibitor, of cysteinyl leukotriene receptor 1 (CysLTR1) but not cysteinyl leukotriene receptor 2 (CysTR2). In consequence, Montelukast blocks the binding and thereby the actions of LTD4, LTC4, and LTE4 that are mediated by CysLTR1. It is presumed to act similarly to block the actions of α-ketoglutarate and itaconate on OXGR1.[1][16][17] It is not yet known if other CysLTR1 inhibitors (see Cysteinyl leukotriene receptor 1#Clinical significance) can mimic Montelukast in blocking OXGR1's responses to α-ketoglutarate and itaconate. Furthermore, Montelukast is used to treat various disorders including asthma, exercise-induced bronchoconstriction, allergic rhinitis, primary dysmenorrhea (i.e. menstrual cramps not associated with known causes, see dysmenorrhea#Causes), and urticaria (see cysteinyl leukotriene receptor 1#Clinical significance). While it is likely that its inhibition of CysLTR1 accounts for its beneficial effects in these diseases, the ability of these leukotrienes, particularly LTB4, to stimulate OXGR1 allows that Montelukast’s beneficial effects on these conditions might reflect at least in part its ability to block not only CysLTR1 but also OXGR1.[1]

Expression[edit]

Based on their content of OXGR1 mRNA, OXGR1 is expressed in human: a) kidney, placenta, and fetal brain; b) tissues involved in allergic and other hypersensitivity reactions such as the lung trachea, salivary glands tissues, and nasal mucosa, particularly the vascular smooth muscle in the latter tissue.[1] and c) cells involved in producing allergic and other hypersensitivity reactions such as eosinophils and mast cells.[18][19] In mice, Oxgr1 mRNA is expressed in kidneys, testes, and smooth muscle.[1]

Functions[edit]

Associated with OXGR1 gene defects[edit]

The following studies have defined OXGR1 functions base on the presence of serious disorders in mice or humans that have that do not have a viable OXGR1 gene and/or protein. It is not been determined which of OXGR1's ligands, if any, are responsible for stimulating OXGR1 to prevent these disorders.

Otitis media[edit]

Mice lacking in OXGPR1 protein due the knockout of their Oxgr1 gene developed (82% penetrance) spontaneous otitis media (i.e., inflammation in their middle ears), mucus effusions in their middle ears, and hearing losses with many characteristics of the human disease. The study did not find evidence that these mice had a middle ear bacterial infection. While the underlying mechanism for the development of this otitis has not been, the study suggest that OXER1 functions to prevent middle ear inflammations and proposes that Oxgr1 gene knockout mice may be a good model to study and relate to human ear pathology.[20]

Kidney stones and nephrocalcinosis[edit]

Majmunda et al. identified 6 individuals from different families with members that had histories of developing calcium-containing kidney stones (also termed nephrolithiasis) and/or nephrocalcinosis (i.e., the deposition of calcium-containing material in multiple sites throughout the kidney). Each of these 6 individuals had dominant variants in their OXGR1 gene. These variant genes were, based on their OXGR1 gene's DNA structure as determined by exome sequencing, to be unable to form an active OXGR1 protein. The study proposed that the OXGR1 gene is a candidate for offsetting the development of calcium-containing nephrolithiasis and nephrocalcinosis in humans.[21]

Associated with α-ketoglutarate-regulated functions[edit]

Studies in rodents have found that the ability of α-ketoglutarate to regulate various functions is dependent on its activation of OXGR1 (see OXGR1 receptor-dependent bioactions of α-ketoglutarate. These functions include: promoting normal kidney functions (e.g., absorption of key urinary ions and maintenance of acid base balance[22]); regulate the development glucose tolerance as defined by glucose tolerance tests;[23][23] suppress the development of diet-induced obesity;[24] and suppressing the muscle atrophy respnse to excessive exercise.[24]

Associated with itaconate-regulated functions[edit]

Check[15] The activation of OXGR1 by itaconate inhibits a wide-range of potentially deleterious inflammatory reactions[25] and suppresses the growth of certain cancers (See Actions of itaconate and its analogs).[26]


References[edit]

  1. ^ a b c d e f g h i Kanaoka Y, Maekawa A, Austen KF (Apr 2013). "Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand". The Journal of Biological Chemistry. 288 (16): 10967–72. doi:10.1074/jbc.C113.453704. PMC 3630866. PMID 23504326.
  2. ^ a b Yamamoto T, Miyata J, Arita M, Fukunaga K, Kawana A (November 2019). "Current state and future prospect of the therapeutic strategy targeting cysteinyl leukotriene metabolism in asthma". Respiratory Investigation. 57 (6): 534–543. doi:10.1016/j.resinv.2019.08.003. PMID 31591069.
  3. ^ a b Grimm PR, Welling PA (September 2017). "α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1". Current Opinion in Nephrology and Hypertension. 26 (5): 426–433. doi:10.1097/MNH.0000000000000353. PMID 28771454.
  4. ^ a b c d Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P (March 2023). "The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response". The Journal of Clinical Investigation. 133 (6). doi:10.1172/JCI160463. PMC 10014103. PMID 36919698.
  5. ^ a b Sasaki F, Yokomizo T (August 2019). "The leukotriene receptors as therapeutic targets of inflammatory diseases". International Immunology. 31 (9): 607–615. doi:10.1093/intimm/dxz044. PMID 31135881.
  6. ^ Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF (2001). "Discovery and mapping of ten novel G protein-coupled receptor genes". Gene. 275 (1): 83–91. doi:10.1016/s0378-1119(01)00651-5. PMID 11574155.
  7. ^ a b Wittenberger T, Hellebrand S, Munck A, Kreienkamp HJ, Schaller HC, Hampe W (July 2002). "GPR99, a new G protein-coupled receptor with homology to a new subgroup of nucleotide receptors". BMC Genomics. 3: 17. doi:10.1186/1471-2164-3-17. PMC 117779. PMID 12098360.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Inbe H, Watanabe S, Miyawaki M, Tanabe E, Encinas JA (2004). "Identification and characterization of a cell-surface receptor, P2Y15, for AMP and adenosine". The Journal of Biological Chemistry. 279 (19): 19790–9. doi:10.1074/jbc.M400360200. PMID 15001573.
  9. ^ Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Miras-Portugal MT, King BF, Gachet C, Jacobson KA, Weisman GA (2005). "The recently deorphanized GPR80 (GPR99) proposed to be the P2Y15 receptor is not a genuine P2Y receptor". Trends in Pharmacological Sciences. 26 (1): 8–9. doi:10.1016/j.tips.2004.10.010. PMC 6905457. PMID 15629198.
  10. ^ He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L (May 2004). "Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors". Nature. 429 (6988): 188–93. doi:10.1038/nature02488. PMID 15141213.
  11. ^ Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ (2013). "International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands". Pharmacological Reviews. 65 (3): 967–86. doi:10.1124/pr.112.007179. PMC 3698937. PMID 23686350.
  12. ^ Gonzalez NS, Communi D, Hannedouche S, Boeynaems JM (December 2004). "The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids". Purinergic Signalling. 1 (1): 17–20. doi:10.1007/s11302-004-5071-6. PMC 2096567. PMID 18404396.
  13. ^ "Oxoglutarate receptor | Oxoglutarate receptor | IUPHAR/BPS Guide to PHARMACOLOGY".
  14. ^ Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE (2014). "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". British Journal of Pharmacology. 171 (15): 3551–74. doi:10.1111/bph.12665. PMC 4128057. PMID 24588652.
  15. ^ a b Ye D, Wang P, Chen LL, Guan KL, Xiong Y (March 2024). "Itaconate in host inflammation and defense". Trends in Endocrinology and Metabolism: TEM. doi:10.1016/j.tem.2024.02.004. PMID 38448252.
  16. ^ Guerrero A, Visniauskas B, Cárdenas P, Figueroa SM, Vivanco J, Salinas-Parra N, Araos P, Nguyen QM, Kassan M, Amador CA, Prieto MC, Gonzalez AA (2021). "α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions". Frontiers in Cardiovascular Medicine. 8: 644797. doi:10.3389/fcvm.2021.644797. PMC 8220822. PMID 34179130.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ Pu S, Zhang J, Ren C, Zhou H, Wang Y, Wu Y, Yang S, Cao F, Zhou H (July 2023). "Montelukast prevents mice against carbon tetrachloride- and methionine-choline deficient diet-induced liver fibrosis: Reducing hepatic stellate cell activation and inflammation". Life Sciences. 325: 121772. doi:10.1016/j.lfs.2023.121772. PMID 37178864.
  18. ^ Steinke JW, Negri J, Payne SC, Borish L (2014). "Biological effects of leukotriene E4 on eosinophils". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 91 (3): 105–10. doi:10.1016/j.plefa.2014.02.006. PMC 4127125. PMID 24768603.
  19. ^ Shirasaki H, Kanaizumi E, Himi T (2016). "Expression and localization of OXGR1 in human nasal mucosa". Auris, Nasus, Larynx. 44 (2): 162–167. doi:10.1016/j.anl.2016.05.010. PMID 27324180.
  20. ^ Kerschner JE, Hong W, Taylor SR, Kerschner JA, Khampang P, Wrege KC, North PE (2013). "A novel model of spontaneous otitis media with effusion (OME) in the Oxgr1 knock-out mouse". International Journal of Pediatric Otorhinolaryngology. 77 (1): 79–84. doi:10.1016/j.ijporl.2012.09.037. PMC 3535456. PMID 23200873.
  21. ^ Majmundar AJ, Widmeier E, Heneghan JF, Daga A, Wu CW, Buerger F, Hugo H, Ullah I, Amar A, Ottlewski I, Braun DA, Jobst-Schwan T, Lawson JA, Zahoor MY, Rodig NM, Tasic V, Nelson CP, Khaliq S, Schönauer R, Halbritter J, Sayer JA, Fathy HM, Baum MA, Shril S, Mane S, Alper SL, Hildebrandt F (March 2023). "OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis". Genetics in Medicine : Official Journal of the American College of Medical Genetics. 25 (3): 100351. doi:10.1016/j.gim.2022.11.019. PMC 9992313. PMID 36571463.
  22. ^ Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D (July 2013). "α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism". The Journal of Clinical Investigation. 123 (7): 3166–71. doi:10.1172/JCI67562. PMC 3696567. PMID 23934124.
  23. ^ a b Yuan Y, Zhu C, Wang Y, Sun J, Feng J, Ma Z, Li P, Peng W, Yin C, Xu G, Xu P, Jiang Y, Jiang Q, Shu G (May 2022). "α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling". Science Advances. 8 (18): eabn2879. doi:10.1126/sciadv.abn2879. PMC 9067931. PMID 35507647.
  24. ^ a b Yuan Y, Xu P, Jiang Q, Cai X, Wang T, Peng W, Sun J, Zhu C, Zhang C, Yue D, He Z, Yang J, Zeng Y, Du M, Zhang F, Ibrahimi L, Schaul S, Jiang Y, Wang J, Sun J, Wang Q, Liu L, Wang S, Wang L, Zhu X, Gao P, Xi Q, Yin C, Li F, Xu G, Zhang Y, Shu G (April 2020). "Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation". The EMBO Journal. 39 (7): e103304. doi:10.15252/embj.2019103304. PMC 7110140. PMID 32104923.
  25. ^ Shi X, Zhou H, Wei J, Mo W, Li Q, Lv X (December 2022). "The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases". Redox Biology. 58: 102553. doi:10.1016/j.redox.2022.102553. PMC 9713374. PMID 36459716.
  26. ^ Yang W, Wang Y, Tao K, Li R (December 2023). "Metabolite itaconate in host immunoregulation and defense". Cellular & Molecular Biology Letters. 28 (1): 100. doi:10.1186/s11658-023-00503-3. PMC 10693715. PMID 38042791.

Further reading[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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