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) 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 be activated by α-ketoglutarate, itaconate, and three cysteinyl-containing leukotrienes (abbreviated as CysLTs), leukotriene E4 (i.e., LTE4), LTC4, and LTD4. 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 that have two carboxyl groups (notated as -CO2H) both of 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 − {\displaystyle ^{-}} ), because they are not bound to H+ (see Conjugate acid-base theory). It is α-ketoglutarate and itaconate, not α-ketoglutaric or itaconic acids, which activate OXGR1.
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 proteins) was identified. Its protein product was classified as an orphan receptor, i.e., a receptor whose activating ligand and function are unknown. The projected 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 purines. This study named the new receptor and its gene GPR80 and GPR80, respectively. 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. 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. 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. A fourth study, also published in 2004, found that GPR80/GPR99 -bearing cells responded to α-ketoglutarate. In 2013, IUPHAR accepted this report and the names OXGR1 and OXGR1 for the α-ketoglutarate responsive receptor and its gene, respectively. In 2013, a fifth study found that LTE4, LTC4, and LTD4 activated OXGR1. Finally, a 2023 study provided evidence that itaconate also activated OXGR1.
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 "q" arm (i.e., long arm) of chromosome 13. 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 Functions of the Gq alpha pathways) that stimulate the cellular responses that these pathways are programmed to elicit.
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 cultures of cells expressing human OXGR1:
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 whereas LTC4, LTD4, α-ketoglutarate, and itaconate require far higher levels to do so. 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:
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