Orexin-A (Hypocretin-1) is a 33-amino acid neuropeptide produced by neurons in the lateral hypothalamus, critical for regulating sleep-wake cycles, arousal, and appetite. Discovery of its role in narcolepsy earned the 2022 Breakthrough Prize.
Discovery (1998)
Two independent groups identified orexins:
- "Orexins" (Greek: orexis = appetite)
- "Hypocretins" (hypothalamic + secretin similarity)
Structure
Sequence: pGlu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2
Key features:
- N-terminal pyroglutamyl residue
- Two intrachain disulfide bonds
- C-terminal amidation
- 100% conserved across mammals
Orexin Neurons
50,000-80,000 neurons in humans, located in perifornical area and lateral hypothalamus, projecting widely throughout CNS.
Physiological Functions
- Sleep-Wake Regulation: Excites arousal systems (noradrenergic, serotonergic, histaminergic)
- Appetite regulation
- Energy expenditure
- Reward processing
Narcolepsy Connection
Narcolepsy Type 1 (NT1)
- Caused by destruction of orexin-producing neurons (autoimmune)
-
90% of NT1 patients have CSF orexin-A <110 pg/mL
- Associated with HLA-DQB1*06:02 allele
Therapeutic Implications
- Orexin Agonists: In development for narcolepsy
- Orexin Antagonists: Approved for insomnia (Suvorexant, Lemborexant, Daridorexant)