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Questions And Answer

• Structure

  Orexin exists as two molecular forms, orexin-A and orexin-B, derived from the same 130-aa residue precursor (prepro-orexin). In mammals, orexin-A is a 33 aa residue peptide with an N-terminal glutamine cyclized to pyroglutamate, and two intrachain disulfide bonds that are fully conserved among tetrapods. Orexin-B is a linear 28 aa residue peptide. Orexin-B consists of two α-helices connected with a short linker. The C-termini of both orexins are amidated. Human orexin-A and orexin-B have 46% homology (13/28), with their C-terminal side in particular being conserved. Although it was thought originally that orexin has no functional or structural identity with any other known regulatory peptide, it is now considered to belong to the incretin gene family of peptides, including members of the secretin-glucagon superfamily such as growth hormone-releasing hormone, pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal peptide, and glucagon-like peptides. The molecular structures of orexins are relatively well conserved among vertebrates, especially in the disulfide bond regions in orexin-A and the C-terminal side in both orexins. Although tetrapod orexin-A comprises 33 aa residues, orexin-A of goldfish and zebrafish is 14 aa residues longer due to an additional spacer sequence.
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• Gene, mRNA, and precursor

  The human prepro-orexin gene (HCRT), located on chromosome 17 (17q21), consists of two exons and one intron. Orexin-A and -B are coded tandemly in the prepro-orexin mRNA. To date, orexin has been identified in vertebrates, but orexin-like sequences have not been identified in invertebrates.
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• Pathophysiological implications

  The dual orexin receptor antagonist suvorexant has been approved by the US Food and Drug Administration (FDA) for insomnia. Dual orexin receptor agonists such as almorexant, lemborexant, filorexant, and SB-649868 have been proceeded clinical trial. Suvorexant and other dual orexin receptor antagonists are being explored in a number of other indications, including depression, anxiety disorders, pain conditions, and degenerative disorders such as Alzheimer’s disease.;

• Synthesis and release

  Orexin-A and orexin-B are synthesized in neurons located in the lateral hypothalamus. Food restriction increases orexin mRNA and peptide content in the brain. In cultured hypothalamic orexin neurons, low glucose concentration in the medium triggers the synthesis of orexins.;

• Receptors

  There are two types of orexin receptors: orexin receptor-1 and -2 (OX1R and OX2R). The orexin receptors are GPCRs with seven-transmembrane domains. The amino acid sequence homology of human orexin receptors is mutually 64%. Orexin-A binds to OX1R and OX2R with a high affinity, whereas orexin-B selectively binds to OX2R with a similar high affinity. The human OX1R gene is located on chromosome 1 (1p35), and the human OX2R gene is located on chromosome 6 (6q11). OX1R and OX2R activate Gq pathways to produce IP3 and an intracellular rise in Ca²⁺, or to stimulate the MAPK pathway. Furthermore, OX2R is able to modulate the intracellular concentration of cAMP by coupling to Gs and Gi proteins.;

• Agonists and Antagonists

  [Ala¹¹, D-Leu¹⁵]-Orexin B and SB-668875 are OX2 specific agonists. Among orexin receptor antagonists, ACT-335827, SB-334867, and SB-408124 are OX1-specific antagonists; TCS-OX2-29, EMPA, and JNJ 10397049 are OX2-specific antagonists; and ACT-078573 (almorexant), MK-4305 (suvorexant), MK-6096 (filorexant), E-2006 (lemborexant), SB-649868, and TCS 1102 are dual antagonists. Further information regarding orexin receptor antagonists can be found in the review by Lebold and colleagues.;

• Biological functions

  Although orexin was first reported as an appetite-stimulating hormone in mammals, further studies have revealed its multifunctional status. An important function of orexin is as a regulator of the sleep-wake cycle. Orexin affects monoaminergic neurons in the locus ceruleus, raphe nucleus, and ventral tegmental area to maintain wakefulness. Orexin systems have roles in regulating drinking behavior, locomotor activity, and sympathetic nervous system activation. Orexin contributes to the regulation of the endocrine system, elevating blood corticosterone levels, decreasing blood prolactin levels, and suppressing the gonadotropin-producing cells in the hypothalamus. In teleosts, the intracerebroventricular injection of orexin-A stimulates food consumption and locomotor activity in goldfish and zebrafish.;

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