orexin2

Orexin receptor type 2, also known as orexin receptor 2 (OX2R) or hypocretin receptor 2 (HCRTR2), is a G protein-coupled receptor that binds the neuropeptides orexin A and orexin B. It is encoded by the HCRTR2 gene in humans and is one of two orexin receptors, the other being OX1R (HCRTR1). OX2R is a seven-transmembrane receptor that, upon activation, couples to intracellular signaling pathways, typically involving Gq/11 proteins and phospholipase C to raise intracellular calcium, with possible coupling to other G proteins in certain cell types.

In the brain, OX2R is widely expressed, with relatively high levels in the tuberomammillary nucleus and notable presence in other arousal-related regions such as the locus coeruleus and dorsal raphe. Orexin-producing neurons in the lateral hypothalamus project broadly throughout the CNS, enabling orexin signaling to influence multiple physiological processes. OX2R participates in the regulation of wakefulness, arousal, energy homeostasis, feeding, reward, and stress responses.

Physiological and clinical relevance of OX2R is most prominently linked to sleep-wake regulation. Disruption of orexin signaling can produce narcolepsy-like phenotypes in animal models, and human narcolepsy type 1 is associated with orexin deficiency. Research into orexin receptors also supports the development of pharmacological agents that modulate sleep, including orexin receptor antagonists that target OX2R (often together with OX1R) to treat insomnia. OX2R remains an active area of study for understanding arousal mechanisms and exploring therapeutic approaches.