G protein-coupled receptor 99 (GPR99) (GPR99)

G protein-coupled receptor 99 (GPR99), also known as oxoglutarate receptor 1 (OXGR1) or cysteinyl leukotriene receptor 3 (CysLT3R), is a cell-surface receptor that has been identified as the high-affinity receptor for leukotriene E4 (LTE4) [1, 5]. While LTE4 was historically viewed as a stable but weak metabolite of the cysteinyl leukotriene pathway, recent research demonstrates that it acts through GPR99 to potently induce airway mucin release, vascular permeability, and the activation of lung brush cells [2, 7]. GPR99 is distinct from the classical CysLT1 and CysLT2 receptors and is notably resistant to current asthma medications like montelukast [7, 12]. Beyond its role in inflammation, GPR99 serves as a sensor for the Krebs cycle intermediate 2-oxoglutarate (alpha-ketoglutarate) in the kidney, where it helps regulate acid-base balance [5, 15]. In the respiratory system, GPR99 is expressed on airway epithelial cells and myoepithelial cells, where it mediates goblet cell hyperplasia and mucus hypersecretion in response to allergens [3, 6]. Because of its specific involvement in LTE4-mediated responses that are not addressed by existing therapies, GPR99 is considered a promising novel therapeutic target for severe asthma and other chronic inflammatory airway diseases [9, 16].

Other names

Oxoglutarate receptor 1OXGR1Cysteinyl leukotriene receptor 3CysLT3RP2Y purinoceptor 15P2Y15

Antagonism of the receptor to block leukotriene E4-mediated inflammatory signaling and mucus hypersecretion.