2-oxoglutarate receptor 1 (OXGR1)

2-oxoglutarate receptor 1 (OXGR1), also known as GPR99, is a G protein-coupled receptor that serves as the primary cell-surface sensor for the citric acid cycle intermediate alpha-ketoglutarate (alpha-KG) [6, 13]. Beyond its role in sensing metabolic status, OXGR1 has been identified as a high-affinity receptor for the inflammatory mediator leukotriene E4 (LTE4), positioning it at the intersection of metabolism and inflammation [20, 32]. In the kidney, OXGR1 is expressed in the distal tubules and collecting ducts, where it regulates acid-base balance and salt reabsorption in response to urinary alpha-KG levels [12, 30]. In the immune system, it mediates allergic and hypersensitivity responses triggered by cysteinyl leukotrienes [24, 32]. While alpha-KG itself is often used as a nutritional supplement to support longevity and muscle health, the receptor is a target of interest for treating asthma and renal disorders [1, 33]. Notably, the leukotriene antagonist montelukast has been shown to inhibit OXGR1, suggesting potential for drug repurposing or the development of more selective antagonists for metabolic and inflammatory diseases [20, 24]. The receptor primarily signals through the Gq/11 pathway, leading to phospholipase C activation and intracellular calcium mobilization [6, 13]. Recent structural studies have elucidated how OXGR1 recognizes its diverse ligands, providing a foundation for rational drug design [32]. Dysregulation of OXGR1 signaling is implicated in conditions ranging from metabolic alkalosis to chronic airway inflammation [12, 20]. As a metabolic and inflammatory sensor, OXGR1 represents a unique therapeutic node for modulating systemic homeostasis [2, 11].

Other names

Alpha-ketoglutarate receptor 1G-protein coupled receptor 99GPR99GPR80P2Y purinoceptor 15P2Y15P2RY15AKGRCysteinyl leukotriene receptor ECysLTECysteinyl leukotriene receptor 3CysLT3

Agonism of the Gq-coupled receptor activates phospholipase C (PLC), leading to the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG), which triggers intracellular calcium release and downstream signaling pathways [6, 13]. Antagonism by drugs like montelukast blocks these signaling events [20, 24].