Orexin/hypocretin receptor type 1 (OX1R)

Orexin/hypocretin receptor type 1 (OX1R) is a G protein-coupled receptor that binds orexin-A with high affinity and orexin-B with lower affinity. It is primarily expressed in brain regions receiving projections from the lateral hypothalamus, especially in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN). OX1R mediates diverse central nervous system functions, including regulation of feeding behavior, sleep-wake cycles, reward pathways, and energy homeostasis. Dysfunction or altered signaling through OX1R has been implicated in narcolepsy, depression, drug addiction, and potentially neurodegenerative diseases and cancer. Selective antagonists and dual antagonists (targeting both OX1R and OX2R) have been developed, with some dual antagonists approved for treating insomnia.

Other names

HCRTR1Hypocretin receptor 1ORXR1OXR1

OX1R primarily couples to Gq proteins but can also signal via Gi/o proteins depending on cell context. Key downstream pathways include Phospholipase C activation (leads to IP₃ production → Ca²⁺ release from intracellular stores), MAPK/ERK pathway (activation leads to phosphorylation cascades affecting gene expression), PI3K/Akt pathway (involved in cell survival/proliferation), cAMP modulation (can both inhibit or stimulate cAMP synthesis depending on context), and PLD/PLA2 signaling (produces lipid second messengers like arachidonic acid).