preproorexin

Preproorexin, also called preprohypocretin, is the precursor polypeptide that gives rise to the orexin (hypocretin) neuropeptides orexin-A and orexin-B. In humans, it is encoded by the HCRT gene. As a secreted precursor, preproorexin contains an N-terminal signal peptide that directs the nascent protein into the secretory pathway, followed by a propeptide region that is cleaved by prohormone convertases to generate the mature orexin peptides. Post-translational modifications further process the cleaved products to yield the active neuropeptides.

The mature orexin-A and orexin-B peptides are produced from preproorexin through proteolytic processing and are released by orexin-producing neurons. These neurons are located primarily in the lateral hypothalamus and perifornical area, and they project widely to many brain regions, including the cortex, brainstem, and limbic structures.

Physiological roles of the orexin system include regulation of wakefulness and arousal, energy homeostasis, feeding behavior, reward, and certain motivated or stress-related responses. The peptides act on two G protein-coupled receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R), which mediate diverse central effects related to vigilance and metabolic state.

Clinical relevance centers on the loss or dysfunction of orexin signaling. Narcolepsy type 1 is strongly associated with loss of orexin-producing neurons, leading to excessive daytime sleepiness and cataplexy. Conversely, pharmacological modulation of the orexin system—such as orexin receptor antagonists used to treat insomnia—highlights the therapeutic significance of the preproorexin–orexin axis. Ongoing research investigates how regulation of preproorexin expression and processing influences sleep, appetite, and metabolic disorders. See also hypocretin, orexin-A, orexin-B, and hypocretin receptors.