2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the (also termed GPR99) gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate (see alpha-Ketoglutaric acid) but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.
History
In 2001, a gene projected to code for a G protein-like receptor protein was reported; the gene's apparent protein product was classified as an orphan receptor (i.e., a receptor whose activating ligand and function were unknown) and named GPR80. The projected amino acid sequence of the protein encoded by the GPR80 gene bore similarities to a purinergic receptor, P2Y1, and therefore might, like P2Y1, be a receptor for purine compounds. Shortly thereafter, a second report found this same gene, indicated that it coded for a G protein receptor with its amino acid sequence similarities closest to purinergic receptors GPR91 and P2Y1, and named the gene and its protein GPR99 and GPR99, respectively. While the latter report found that a large series of purinergic nucleotides, other nucleotides, and derivatives of these compounds did not activate GPR99-bearing cells, a third report in 2004 found that GPR99-bearing cells bound and responded to two purines, adenosine and Adenosine monophosphate, nominated GPR99 as a true purinergic receptor, and renamed GPR99 as P2Y15. However, a review of these studies in the same year by members of the International Union of Pharmacology (IUPHAR) Subcommittee for P2Y receptor nomenclature and classification decided that GPR80/GPR99 is not a P2Y receptor for adenosine, AMP or other nucleotides. Again in 2004, another report found that GPR99-bearing cells responded to alpha-ketoglutarate. This report was accepted by IUPHAR. The gene and its protein were renamed OXGR1 and OXGR1. Finally, in 2013, GPR99-bearing cells were found to bind and respond to CysLTs. The latter finding, while attracting further studies and of potential clinical importance, has not yet lead to a renaming of GPR99 nor its protein product.
Gene and product
GPR99 (OXGR1) is localized to human chromosome 13 at position 13q32.2; it codes for a cellular G protein coupled receptor linked primarily to G protein heterotrimers containing the Gq subunit; when bound to one of its activating ligands, the GPR99 protein stimulates cellular pathways (see Gq alpha subunit#Function) that lead to cell function.
Activating ligands
GPR99 appears to be the receptor for alpha-ketoglutarate (AKG) and CysLTs. CyslTs and AKG have the following relative potencies in binding to GPR99-bearing cells, LTE4>>LTC4=LTD4>AKG; LTE4 is able to stimulate responses in these cells at concentrations as low as picomole/liter.
Inhibiting ligands
GPR99 is inhibited by montelukast, a well-known and clinically useful inhibitor of cysteinyl leukotriene receptor 1 (CysLTR1); this drug binds to CysLTR1 thereby blocking the binding and action of LTD4, LTC4, and LTE4. It is presumed to act similarly to block the actins of these cystienyl leukotrienes on GPR99. It is not known if other CysLTR1 inhibitors (see Cysteinyl leukotriene receptor 1#Clinical significance) can mimic montelukast in blocking GPR99.
Expression
Based on their content of GPR99 mRNA, GPR99 is expressed in human kidney, placenta, fetal brain, and tissues involved in allergic and hypersensitivity reactions such as the lung trachea, salivary glands, eosinophils, mast cells derived from umbilical cord blood, and nasal mucosa, particularly the vascular smooth muscle in the latter tissue. In mice, Gpr99 mRNA is expressed in kidneys, testes, and smooth muscle.