View source for OXGR1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''OXGR1''', i.e., '''2-oxoglutarate receptor 1''' (also known as GPR99, cysteinyl leukotriene receptor E, i.e., CysLT<sub>E</sub>, and cysteinyl leukotriene receptor 3, i.e., CysLT3<ref name="pmid23504326">{{cite journal | vauthors = Kanaoka Y, Maekawa A, Austen KF | title = Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand | journal = The Journal of Biological Chemistry | volume = 288 | issue = 16 | pages = 10967–72 | date = April 2013 | pmid = 23504326 | pmc = 3630866 | doi = 10.1074/jbc.C113.453704 | doi-access = free | url = }}</ref><ref name="pmid31591069">{{cite journal | vauthors = Yamamoto T, Miyata J, Arita M, Fukunaga K, Kawana A | title = Current state and future prospect of the therapeutic strategy targeting cysteinyl leukotriene metabolism in asthma | journal = Respiratory Investigation | volume = 57 | issue = 6 | pages = 534–543 | date = November 2019 | pmid = 31591069 | doi = 10.1016/j.resinv.2019.08.003 | url = }}</ref>) is a [[G protein-coupled receptor]] located on the [[cell surface membrane|surface membrane]]s of certain cells. It functions by binding one of its [[Ligand (biochemistry)|ligands]] and thereby becoming active in triggering pre-programmed responses in its parent cells. OXGR1 has been shown to be activated by α-ketoglutarate,<ref name="pmid28771454">{{cite journal | vauthors = Grimm PR, Welling PA | title = α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1 | journal = Current Opinion in Nephrology and Hypertension | volume = 26 | issue = 5 | pages = 426–433 | date = September 2017 | pmid = 28771454 | doi = 10.1097/MNH.0000000000000353 | url = }}</ref> itaconate,<ref name="pmid36919698">{{cite journal | vauthors = Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P | title = The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response | journal = The Journal of Clinical Investigation | volume = 133 | issue = 6 | pages = | date = March 2023 | pmid = 36919698 | pmc = 10014103 | doi = 10.1172/JCI160463 | url = }}</ref> and three [[Cysteine|cysteinyl]]-containing [[leukotrienes]] (abbreviated as CysLTs), [[leukotriene E4]] (i.e., LTE4), [[LTC4]], and [[LTD4]].<ref name="pmid23504326"/><ref name="pmid31135881">{{cite journal | vauthors = Sasaki F, Yokomizo T | title = The leukotriene receptors as therapeutic targets of inflammatory diseases | journal = International Immunology | volume = 31 | issue = 9 | pages = 607–615 | date = August 2019 | pmid = 31135881 | doi = 10.1093/intimm/dxz044 | url = }}</ref> α-Ketoglutarate and itaconate are the [[dianion]]ic forms of [[alpha-ketoglutaric acid|α-ketoglutaric acid]] and [[itaconic acid]], respectively. α-Ketoglutaric and itaconic acids are short-chain [[dicarboxylic acid]]s that have two [[carboxyl group]]s (notated as -{{chem2|CO2H}}) both of which are bound to [[hydrogen]] (i.e., {{chem2|H+}}). However, at the [[Base (chemistry)|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 -{{chem2|CO2}}<math>^{-}</math>), because they are not bound to {{chem2|H+}} (see [[Conjugate (acid-base theory)|Conjugate acid-base theory]]). It is α-ketoglutarate and itaconate, not α-ketoglutaric or itaconic acids, which activate OXGR1.<ref name="pmid28771454"/><ref name="pmid36919698"/>

== History ==
In 2001, a human gene projected to code for a G protein-coupled receptor (i.e., a receptor that stimulates cells by activating [[G protein]]s) was identified. Its [[protein]] product was classified as an [[orphan receptor]], i.e., a receptor whose activating ligand and function are unknown. The projected [[Protein primary structure|amino acid sequence]] of the protein encoded by this gene bore similarities to the [[purinergic receptor]], [[P2Y1]], and therefore might, like P2Y1, be a receptor for [[purine]]s. This study named the new receptor and its gene GPR80 and ''GPR80'', respectively.<ref name="pmid11574155">{{cite journal | vauthors = Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF | title = Discovery and mapping of ten novel G protein-coupled receptor genes | journal = Gene | volume = 275 | issue = 1 | pages = 83–91 | year = 2001 | pmid = 11574155 | doi = 10.1016/s0378-1119(01)00651-5}}</ref> 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 receptor]]s, P2Y1 and [[SUCNR1|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.<ref name="pmid12098360"/> 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 two purines, [[adenosine]] and [[adenosine monophosphate]]. The study nominated this receptor to be a purinergic receptor and named it the P2Y15 receptor.<ref name="pmid15001573">{{cite journal | vauthors = Inbe H, Watanabe S, Miyawaki M, Tanabe E, Encinas JA | title = Identification and characterization of a cell-surface receptor, P2Y15, for AMP and adenosine | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 19790–9 | year = 2004 | pmid = 15001573 | doi = 10.1074/jbc.M400360200 | doi-access = free }}</ref> However, a review in 2004 of these three studies 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.<ref name="pmid15629198">{{cite journal | vauthors = Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Miras-Portugal MT, King BF, Gachet C, Jacobson KA, Weisman GA | title = The recently deorphanized GPR80 (GPR99) proposed to be the P2Y15 receptor is not a genuine P2Y receptor | journal = Trends in Pharmacological Sciences | volume = 26 | issue = 1 | pages = 8–9 | year = 2005 | pmid = 15629198 | doi = 10.1016/j.tips.2004.10.010 | pmc = 6905457 }}</ref> A fourth study, also published in 2004, found that GPR80/GPR99 -bearing cells responded to α-ketoglutarate.<ref name="pmid15141213">{{cite journal | vauthors = He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L | title = Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors | journal = Nature | volume = 429 | issue = 6988 | pages = 188–93 | date = May 2004 | pmid = 15141213 | doi = 10.1038/nature02488 | bibcode = 2004Natur.429..188H | url = }}</ref> In 2013, IUPHAR accepted this report and the names OXGR1 and ''OXGR1'' for the α-ketoglutarate responsive receptor and its gene, respectively.<ref name="pmid23686350">{{cite journal | vauthors = 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 | title = International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands | journal = Pharmacological Reviews | volume = 65 | issue = 3 | pages = 967–86 | year = 2013 | pmid = 23686350 | pmc = 3698937 | doi = 10.1124/pr.112.007179 }}</ref> In 2013, a fifth study found that LTE4, LTC4, and LTD4 activated OXGR1.<ref name="pmid23504326"/> Finally, a 2023 study provided evidence that [[itaconate]] also activated OXGR1.<ref name="pmid36919698"/><ref name="pmid38448252">{{cite journal | vauthors = Ye D, Wang P, Chen LL, Guan KL, Xiong Y | title = Itaconate in host inflammation and defense | journal = Trends in Endocrinology and Metabolism | volume = | issue = | pages = | date = March 2024 | pmid = 38448252 | doi = 10.1016/j.tem.2024.02.004 | url = }}</ref>

== ''OXGR1'' gene ==
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  [[Locus (genetics)#Nomenclature|"q" arm]] (i.e., long arm) of chromosome 13.<ref name="pmid12098360">{{cite journal | vauthors = Wittenberger T, Hellebrand S, Munck A, Kreienkamp HJ, Schaller HC, Hampe W | title = GPR99, a new G protein-coupled receptor with homology to a new subgroup of nucleotide receptors | journal = BMC Genomics | volume = 3 | issue = | pages = 17 | date = July 2002 | pmid = 12098360 | pmc = 117779 | doi = 10.1186/1471-2164-3-17 | doi-access = free | url = }}</ref><ref name="pmid18404396">{{cite journal | vauthors = Gonzalez NS, Communi D, Hannedouche S, Boeynaems JM | title = The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids | journal = Purinergic Signalling | volume = 1 | issue = 1 | pages = 17–20 | date = December 2004 | pmid = 18404396 | pmc = 2096567 | doi = 10.1007/s11302-004-5071-6 | url = }}</ref> ''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 one of its ligands, OXGR1 activates Gq alpha subunit-regulated cellular pathways (see [[Gq alpha subunit#Function|Functions of the Gq alpha pathways]]) that stimulate the cellular responses that these pathways are programmed to elicit.<ref>{{Cite web|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=162|title = Oxoglutarate receptor &#124; Oxoglutarate receptor &#124; IUPHAR/BPS Guide to PHARMACOLOGY}}</ref><ref name="pmid24588652">{{cite journal | vauthors = Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE | title = Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7 | journal = British Journal of Pharmacology | volume = 171 | issue = 15 | pages = 3551–74 | year = 2014 | pmid = 24588652 | pmc = 4128057 | doi = 10.1111/bph.12665 }}</ref>

== OXGR1 activating and inhibiting ligands ==
=== Activating ligands ===
OXGR1 is the receptor for α-ketoglutarate, LTE4, LTC4, LTD4, and itaconate. These ligands have the following relative potencies in stimulating responses in [[Cell culture|cultures]] of cells expressing human OXGR1:<ref name="pmid36919698"/>

::::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 [[picomole]]s/liter<ref name="pmid23504326"/><ref name="pmid36919698"/> whereas LTC4, LTD4, α-ketoglutarate, and itaconate require far higher levels to do so.<ref name="pmid31591069"/><ref name="pmid38448252"/>

The relative potencies that LTC4, LTD4, and LTE4 have in activating their target receptors, i.e., [[cysteinyl leukotriene receptor 1]] (CysLTR1), [[cysteinyl leukotriene receptor 2]] (CysLTR2), and  OXGR1 are:<ref name="pmid31591069"/>

::::CysLTR1: LTD4 > LTC4 >> LTE4
::::CysLTR2: LTC4 = LTD4 >> LTE4	
::::OXGR1:  LTE4 > LTC4 > LTD4

These relationships suggest that CysTR1 and CysLTR2 are physiological receptors for LTD4 and LTC4 but due to its relative weakness in stimulating these two  receptors, perhaps not or to a far lesser extent for LTE4. Indeed, the LTE4 concentrations needed to activate CysTR1 and CysLTR2 may be higher than those that normally occur ''[[in vivo]]'' (see [[Cysteinyl leukotriene receptor 1#Function|Functions of OXGR1 in mediating the actions of LTE4, LTD4, and LTC4]]). These potency relationships suggest that the LTE4's actions are mediated primarily by OXGR1. The following findings support this suggestion. '''First,''' pretreatment of guinea pig trachea and human bronchial smooth muscle with LTE4 but not with LTC4 or LTD4 enhanced their smooth muscle contraction responses to [[histamine]]. This suggests LTE4's target receptor differs from the receptors targeted by LTC4 and LTD4. '''Second,''' LTE4 was as potent as LTC4 and LTD4 in eliciting vascular leakage when injected into the skin of guinea pigs and humans; the inhalation of LTE4 by asthmatic individuals caused the accumulation of [[eosinophil]]s and [[basophil]]s in their bronchial mucosa whereas the inhalation of LTD4 did not have this effect; and mice engineered to lack CysLTR1 and CysLTR2 receptors exhibited edema responses to the intradermal injection of LTC4, LTD4, and LTE4 but LTE4 was 64-fold more potent in triggering this response in these mice than in [[wild type]] mice. Since LTE4 should have been far less active than LTC4 or LTD4 in triggering vascular leakage, the recruitment of the cited cells into the lung, and causing vascular edema responses in mice lacking CysLT1 and CysLT2 receptors, these findings imply that the latter two receptors are not the primary receptors mediating LTF4' actions. And '''third,''' mice engineered to lack all three CysLTR1, CysLTR2, and OXGR1 receptors did not exhibit dermal edema responses to the injection of LTC4, LTD4, or LTE4 thereby indicating that at least one of these receptors was responsible for each of their actions. Overall, these findings suggest that LTE4 commonly acts through a different receptor than LTC4 and LTD4 and that this receptor is OXGR1.<ref name="pmid23504326"/><ref name="pmid31135881"/><ref name="pmid18931305">{{cite journal | vauthors = Maekawa A, Kanaoka Y, Xing W, Austen KF | title = Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 43 | pages = 16695–700 | date = October 2008 | pmid = 18931305 | pmc = 2575482 | doi = 10.1073/pnas.0808993105 | doi-access = free | url = }}</ref> Indeed, studies have defined OXGR1 as the high affinity receptor for LTF4.<ref name="pmid31135881"/><ref name="pmid30291131">{{cite journal | vauthors = Bankova LG, Dwyer DF, Yoshimoto E, Ualiyeva S, McGinty JW, Raff H, von Moltke J, Kanaoka Y, Frank Austen K, Barrett NA | title = The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation | journal = Science Immunology | volume = 3 | issue = 28 | pages = | date = October 2018 | pmid = 30291131 | pmc = 6599626 | doi = 10.1126/sciimmunol.aat9453 | url = }}</ref> Nonetheless, several studies have reported that cultures of certain types of inflammatory cells, e.g., the human  LAD2 (but not LUVA) [[mast cell]] lines,<ref name="pmid26830450">{{cite journal | vauthors = Foster HR, Fuerst E, Branchett W, Lee TH, Cousins DJ, Woszczek G | title = Leukotriene E4 is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression | journal = Scientific Reports | volume = 6 | issue = | pages = 20461 | date = February 2016 | pmid = 26830450 | pmc = 4735867 | doi = 10.1038/srep20461 | url = }}</ref> [[T helper cell]] lymphocytes that have differentiated into T<sub>h</sub>2 cells,<ref name="pmid22391114">{{cite journal | vauthors = Parmentier CN, Fuerst E, McDonald J, Bowen H, Lee TH, Pease JE, Woszczek G, Cousins DJ | title = Human T(H)2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1 | journal = The Journal of Allergy and Clinical Immunology | volume = 129 | issue = 4 | pages = 1136–42 | date = April 2012 | pmid = 22391114 | doi = 10.1016/j.jaci.2012.01.057 | url = }}</ref> and mouse [[ILC2]] lymphocytes (also termed type 2 innate lymphoid cells)<ref name="pmid23688412">{{cite journal | vauthors = Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH | title = Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production | journal = The Journal of Allergy and Clinical Immunology | volume = 132 | issue = 1 | pages = 205–13 | date = July 2013 | pmid = 23688412 | pmc = 3704056 | doi = 10.1016/j.jaci.2013.03.048 | url = }}</ref> The levels of LTE4 used in some of these studies may not develop in animals or humans. In all events, dysfunctions caused by deleting the ''OXGR1'' gene in cells, tissues or animals and dysfunctions in humans that are associated with a lack of a viable ''OXGR1'' gene implicate the lack of OXGR1 protein in the development of these dysfunctions.<ref name="pmid31135881"/><ref name="pmid26830450"/>

=== Inhibiting ligand ===
OXGR1 is inhibited by [[Montelukast]], a well-known and clinically useful [[receptor antagonist]], i.e., inhibitor, of CysLTR1 but not CysTR2 activation. (Inhibitors of CysLTR2 have not been identified.<ref name="pmid37178864">{{cite journal | vauthors = Pu S, Zhang J, Ren C, Zhou H, Wang Y, Wu Y, Yang S, Cao F, Zhou H | title = Montelukast prevents mice against carbon tetrachloride- and methionine-choline deficient diet-induced liver fibrosis: Reducing hepatic stellate cell activation and inflammation | journal = Life Sciences | volume = 325 | issue = | pages = 121772 | date = July 2023 | pmid = 37178864 | doi = 10.1016/j.lfs.2023.121772 | url = }}</ref>) In consequence, Montelukast blocks the binding and thereby the actions of LTE4, LTC4, and LTD4 that are mediated by OXGR1. It is presumed to act similarly to block the actions of α-ketoglutarate and itaconate on OXGR1.<ref name="pmid23504326"/><ref name="pmid34179130">{{cite journal | vauthors = 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 | title = α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions | journal = Frontiers in Cardiovascular Medicine | volume = 8 | issue = | pages = 644797 | date = 2021 | pmid = 34179130 | pmc = 8220822 | doi = 10.3389/fcvm.2021.644797 | doi-access = free | url = }}</ref> It is not yet known if other CysLTR1 inhibitors can mimic Montelukast in blocking OXGR1's responses to α-ketoglutarate and itaconate. 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|causes of dysmenorrhea]]), and [[urticaria]] (see [[cysteinyl leukotriene receptor 1#Function|Functions of CysLTR1]]). While it is likely that its inhibition of CysLTR1 accounts for its effects in these diseases, the ability of these leukotrienes, particularly LTE4, to stimulate OXGR1 allows that Montelukast's effects on these conditions may be due at least in part to its ability to block OXGR1.<ref name="pmid23504326"/>

== Expression ==
Based on their content of the OXGR1 protein or [[mRNA]] that directs its synthesis, OXGR1 is expressed in human: '''a)''' kidney, placenta, and [[fetal]] brain; '''b)''' cells that promote [[allergy|allergic]] and other [[hypersensitivity]] reactions, i.e., [[eosinophils]] and [[mast cells]]; '''c)'''  tissues involved in allergic and other hypersensitivity reactions such as the lung trachea, salivary glands, and nasal [[mucosa]];<ref name="pmid23504326"/><ref name="pmid24768603">{{cite journal | vauthors = Steinke JW, Negri J, Payne SC, Borish L | title = Biological effects of leukotriene E4 on eosinophils | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 91 | issue = 3 | pages = 105–10 | year = 2014 | pmid = 24768603 | pmc = 4127125 | doi = 10.1016/j.plefa.2014.02.006 }}</ref><ref name="pmid27324180">{{cite journal | vauthors = Shirasaki H, Kanaizumi E, Himi T | title = Expression and localization of OXGR1 in human nasal mucosa | journal = Auris, Nasus, Larynx | year = 2016 | volume = 44 | issue = 2 | pages = 162–167 | pmid = 27324180 | doi = 10.1016/j.anl.2016.05.010 }}</ref> and '''d)''' [[fibroblast]]s, i.e., cells that synthesize the [[extracellular matrix]] and [[collagen]] (when pathologically activated, these cells produce tissue [[fibrosis]]).<ref name="pmid37178864"/> In mice, Oxgr1 [[mRNA]] is highly expressed in kidneys, testes, smooth muscle tissues,<ref name="pmid23504326"/> nasal [[epithelial]] cells, and lung epithelial cells.<ref name="pmid27185938">{{cite journal | vauthors = Bankova LG, Lai J, Yoshimoto E, Boyce JA, Austen KF, Kanaoka Y, Barrett NA | title = Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 22 | pages = 6242–7 | date = May 2016 | pmid = 27185938 | pmc = 4896673 | doi = 10.1073/pnas.1605957113 | doi-access = free | url = }}</ref>

== Functions ==
=== Associated with OXGR1 gene defects or deficiencies ===
The following studies have defined OXGR1 functions based on the presence of disorders in mice or humans that do not have a viable OXGR1 protein. It is not been determined which of OXGR1's ligands, if any, are responsible for stimulating OXGR1 to prevent these disorders.

==== Otitis media ====
Mice lacking OXGPR1 protein due the [[gene knockout|knockout]] of their ''OXGR1'' gene developed (82% [[penetrance]]) [[otitis media]] (i.e., inflammation in their [[middle ear]]s), [[mucus]] [[effusion]]s in their middle ears, and hearing losses all which had many characteristics of human otitis media. The study did not find evidence that these mice had a middle ear bacterial infection. (Infection with ''[[Streptococcus pneumoniae]], [[Moraxella catarrhalis]]'', or other bacteria is one of the most common causes of otitis media.<ref name="pmid30084766">{{cite journal | vauthors = Mittal R, Parrish JM, Soni M, Mittal J, Mathee K | title = Microbial otitis media: recent advancements in treatment, current challenges and opportunities | journal = Journal of Medical Microbiology | volume = 67 | issue = 10 | pages = 1417–1425 | date = October 2018 | pmid = 30084766 | doi = 10.1099/jmm.0.000810 | url = }}</ref>) While the underlying mechanism for the development of this otitis has not been well-defined, the study suggests that OXER1 functions to prevent middle ear inflammations and ''Oxgr1'' gene knockout mice may be a good model to study and relate to human ear [[pathophysiology]].<ref name="pmid23200873">{{cite journal | vauthors = Kerschner JE, Hong W, Taylor SR, Kerschner JA, Khampang P, Wrege KC, North PE | title = A novel model of spontaneous otitis media with effusion (OME) in the Oxgr1 knock-out mouse | journal = International Journal of Pediatric Otorhinolaryngology | volume = 77 | issue = 1 | pages = 79–84 | year = 2013 | pmid = 23200873 | pmc = 3535456 | doi = 10.1016/j.ijporl.2012.09.037 }}</ref>

==== Goblet cells ====
Mice lacking OXGR1 protein due the knockout of their '''OXGR1''' gene had significantly fewer numbers of mucin-containing [[goblet cells]] in their nasal mucosa than control mice. ''Cysltr1'' gene knockout mice and ''Cysltr2'' gene knockout mice had normal numbers of these nasal goblet cells. This finding implicates OXGR1 in functioning to maintain higher numbers of airway goblet cells.<ref name="pmid27185938"/>

==== Kidney stones and nephrocalcinosis ====
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 [[Dominance (genetics)|dominant]] variants in their ''OXGR1'' gene. These variant genes appeared (based on their ''OXGR1'' gene's DNA structure as defined by [[exome sequencing]]) to be unable to form an active OXGR1 protein. The study proposed that the ''OXGR1'' gene is a candidate for functioning to suppress the development of calcium-containing nephrolithiasis and nephrocalcinosis in humans.<ref name="pmid36571463">{{cite journal | vauthors = 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 | title = OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis | journal = Genetics in Medicine | volume = 25 | issue = 3 | pages = 100351 | date = March 2023 | pmid = 36571463 | pmc = 9992313 | doi = 10.1016/j.gim.2022.11.019 | url = }}</ref>

=== Associated with α-ketoglutarate-regulated functions ===
Studies in rodents have found that the ability of α-ketoglutarate to regulate various functions is dependent on its activation of OXGR1 (see [[alpha-ketoglutarate#OXGR1 receptor-dependent bioactions|OXGR1 receptor-dependent bioactions of α-ketoglutarate]]). These functions include: promoting normal kidney functions such as the absorption of key urinary ions and maintenance of [[Acid-base homeostasis|acid base balance]];<ref name="pmid23934124">{{cite journal | vauthors = Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D | title = α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism | journal = The Journal of Clinical Investigation | volume = 123 | issue = 7 | pages = 3166–71 | date = July 2013 | pmid = 23934124 | pmc = 3696567 | doi = 10.1172/JCI67562 | url = }}</ref> regulating the development of glucose tolerance as defined by [[glucose tolerance test]]s;<ref name="pmid35507647">{{cite journal | vauthors = 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 | title = α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling | journal = Science Advances | volume = 8 | issue = 18 | pages = eabn2879 | date = May 2022 | pmid = 35507647 | pmc = 9067931 | doi = 10.1126/sciadv.abn2879 | bibcode = 2022SciA....8N2879Y | url = }}</ref> suppressing the development of diet-induced obesity;<ref name="pmid32104923">{{cite journal | vauthors = 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 | title = Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation | journal = The EMBO Journal | volume = 39 | issue = 7 | pages = e103304 | date = April 2020 | pmid = 32104923 | pmc = 7110140 | doi = 10.15252/embj.2019103304 | url = }}</ref> and suppressing the muscle [[atrophy]] response to excessive exercise.<ref name="pmid32104923"/>

=== Associated with LTE4-induced functions ===
A study showed that LTE4, LTC4, and LTD4 produce similar levels of vascular leakage and localized tissue swelling when injected into the skin of guinea pigs or humans. Studies that examined the effects of using various doses of these LTs after injection into the [[earlobes]] of mice found that, in comparison to control mice, OXGR1 gene knockout mice showed virtually no response to injection of a low dose of LTE4, a greatly reduced response to injection of an intermediate dose of LTE4, and a somewhat delayed but otherwise similar response to a high dose of LTE4 (these doses were 0.008, 0.0625, and 0.5 nmols, respectively). The study concluded that lower levels of LTE4 act primarily through OXGR1 to cause vascular permeability and, since it is the major cysteinyl leukotriene that accumulates in inflamed tissues, suggested that OXGR1 may be a therapeutic target for treating inflammatory disorders.<ref name="pmid23504326"/> Another study found that the application of an extract of ''[[Alternaria alternata]]'' (a [[genus]] of [[fungi]] that infects plants and causes allergic diseases, infections, and toxic reactions in animals and humans<ref name="pmid35330279">{{cite journal | vauthors = Sánchez P, Vélez-Del-Burgo A, Suñén E, Martínez J, Postigo I | title = Fungal Allergen and Mold Allergy Diagnosis: Role and Relevance of Alternaria alternata Alt a 1 Protein Family | journal = Journal of Fungi | volume = 8 | issue = 3 | date = March 2022 | page = 277 | pmid = 35330279 | pmc = 8954643 | doi = 10.3390/jof8030277 | doi-access = free | url = }}</ref>) into the noses of mice caused their nasal epithelial cells to release mucin and their nasal [[submucosa]] to swell. (The nasal as well as lung epithelial cells of these mice expressed OXGR1). ''OXGR1'' gene knockout mice did not show these responses to the fungal toxin. The study also showed that '''a)''' ''Cysltr1'' and ''Cysltr2'' double gene knockout mice had full mucin release response to the toxin and '''b)''' Cstlr2 gene knockout mice had full submucosal swelling responses to the toxin but Csltr1 gene knockout mice did not show submucosal swelling responses to the toxin. The study concluded that LTE4's activation of OXGR1 controls key airway epithelial cell functions in mice and suggested that the inhibition of LTE4-induced OXGR1 activation may prove useful for treating asthma and other allergic and inflammatory disorders.<ref name="pmid27185938"/> A subsequent study examined the effects of LTE4-OXGR1 on a certain type of [[tuft cell]]. When located in intestinal [[mucosa]], these tuft cells are termed tuft cells but when located in the nasal respiratory mucosa they are termed solitary chemosensory cells and when located in the trachea they are termed brush cells.<ref name="pmid31953256">{{cite journal | vauthors = Ualiyeva S, Hallen N, Kanaoka Y, Ledderose C, Matsumoto I, Junger WG, Barrett NA, Bankova LG | title = Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2 | journal = Science Immunology | volume = 5 | issue = 43 | pages = | date = January 2020 | pmid = 31953256 | pmc = 7176051 | doi = 10.1126/sciimmunol.aax7224 | url = }}</ref> Control mice that inhaled the mold ''Alternaria alternata'', the American house dust mite ''[[Dermatophagoides farinae]]'', or LTF4 developed increases in the number of their tracheal brush cells, release of the inflammation-promoting cytokine, [[interleukin 25]], and lung inflammation whereas ''OXGR1'' gene knockout mice did not show these responses. These findings indicate that the activation of OXGR1 regulates airway: brush cell numbers, interleukin 25 release, and inflammation.<ref name="pmid30291131"/>

=== Associated with itaconate-regulated functions ===
A study reported in 2023 was the first and to date (2024) only study indicating that itaconate's actions are mediated by activating OXGR1. This study showed that itaconate stimulated the nasal secretion of [[mucus]] when applied to the noses of mice, reduced the number of ''Pseudomonas aeruginosa'' bacteria in their lung tissue and [[bronchoalveolar lavage]] fluid (i.e., airway washing) in mice injected intranasally with these bacteria, and stimulated cultured mouse [[respiratory epithelium]] cells to raise their cytosolic Ca<sup>2+</sup> levels (an indicator of cell activation). Itaconate was unable to induce these responses in ''OXGR1'' gene knockout mice or in the respiratory epithelial cells isolated from the ''OXGR1'' gene knockout mice. The study concluded that the activation of OXGR1 by itaconate contributes to regulating the pulmonary innate immune response to ''Pseudomonas aeruginosa'' and might also do so in other bacterial infections.<ref name="pmid36919698"/><ref name="pmid38448252"/>

== References ==
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== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF | title = Discovery and mapping of ten novel G protein-coupled receptor genes | journal = Gene | volume = 275 | issue = 1 | pages = 83–91 | date = Sep 2001 | pmid = 11574155 | doi = 10.1016/S0378-1119(01)00651-5 }}
* {{cite journal | vauthors = Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S | title = Identification of G protein-coupled receptor genes from the human genome sequence | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 97–101 | date = Jun 2002 | pmid = 12044878 | doi = 10.1016/S0014-5793(02)02775-8 | doi-access = free | bibcode = 2002FEBSL.520...97T }}
* {{cite journal | vauthors = Inbe H, Watanabe S, Miyawaki M, Tanabe E, Encinas JA | title = Identification and characterization of a cell-surface receptor, P2Y15, for AMP and adenosine | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 19790–9 | date = May 2004 | pmid = 15001573 | doi = 10.1074/jbc.M400360200 | doi-access = free }}
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{{G protein-coupled receptors}}

[[Category:G protein-coupled receptors]]