Orexin receptor (OXR) (OXR)

The peripheral orexin receptors, primarily Orexin receptor type 1 (OX1R) and Orexin receptor type 2 (OX2R), are G protein-coupled receptors (GPCRs) that mediate the physiological effects of the neuropeptides orexin-A and orexin-B in tissues outside the central nervous system (UniProt P48346, O43612). While orexin signaling is most recognized for its role in regulating the sleep-wake cycle within the hypothalamus, these receptors are also widely expressed in the gastrointestinal tract, pancreas, adrenal glands, and adipose tissue (PubMed: 22431254). In these peripheral sites, orexin receptors play a crucial role in energy homeostasis, modulating glucose-stimulated insulin secretion, gastric motility, and the release of glucocorticoids (PubMed: 16644694). Dysregulation of peripheral orexin signaling has been implicated in the pathogenesis of metabolic disorders such as obesity and type 2 diabetes, as well as in certain types of cancer and inflammatory bowel diseases (PubMed: 28935956). Most currently approved drugs targeting orexin receptors, such as suvorexant and lemborexant, are dual orexin receptor antagonists (DORAs) used to treat insomnia by acting on central receptors. However, there is significant therapeutic interest in developing peripherally restricted orexin receptor ligands to treat metabolic and digestive conditions while avoiding the sedative side effects associated with crossing the blood-brain barrier.

Other names

Orexin receptor type 1Orexin receptor type 2Hypocretin receptorHCRTR1HCRTR2OX1ROX2RPeripheral orexin receptor

Antagonism or agonism of the G protein-coupled orexin receptors (OX1R and OX2R), which typically couple to Gq/11 or Gi/o proteins to regulate intracellular calcium levels and other secondary messenger systems.