Orexin Receptor 2 (OX2R) (also known as hypocretin receptor 2) is one of two receptors that recognize the peptide neurotransmitters orexin A and orexin B.¹ Orexin A and B are 33 and 28 amino acids in length, respectively, and are derived from a common precursor termed prepro-orexin.

OX2R binds both orexin A and B with similar affinities while OX1R binds orexin A with greater affinity than orexin B (a one order of magnitude difference).^2,3

Both OX2R and OX1R belong to the 7-transmembrane domain, G protein-coupled receptor (GPCR) superfamily. OX2R is thought to transmit signals through the Ga₁₁ class of G proteins, resulting in the activation of phospholipase C with subsequent triggering of the phosphatidylinositol cascade and an influx of extracellular Ca²⁺, probably through transient receptor potential (TRP) channels. OX2R can also transmit signals through inhibitory G_i G proteins, although the mechanism is less well understood.^2,3

The physiological functions of the orexin system (OX1R, OX2R, and their ligands) have been a matter of intense research over the last few years. OX2R is expressed in both the central nervous system and peripheral locations such as gastrointestinal tissues, pancreas, and testis.²

The best studied physiological role of OX2R is its involvement in the regulation of sleep and wakefulness states. Studies in mice lacking the orexin gene and dogs expressing a null mutation of the OX2R show a remarkably similar phenotype to human narcolepsy, a condition characterized by excessive daytime sleepiness, inability to maintain vigilant states, and defects in the regulation of rapid eye movement (REM) sleep.⁴

In addition, the orexin system is involved in regulating autonomic functions such as blood pressure and heart rate, as well as in mechanisms that regulate the reward response in the brain.⁴