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hypocretin; orexin (HCRT, OX, PPORX, PPOX)

Function: - precursor to peptide neurotransmitters - may play a role in sleep - may play role in appetite - may have broader role in homeostatic regulation of a) energy metabolism b) autonomic function, c) hormonal balance d) regulation of body fluids - preprohypocretin gives rise to orexin-A (Hcrt1) & orexin-B (Hcrt2) - orexin-A binds to both OX1R & OX2R with a high affinity - orexin-B binds only to OX2R with a similar high affinity - specific enzymatic cleavages at paired basic residues yield the different active peptides Structure: - structurally similar to secretin - belongs to the orexin family Compartment: - rough endoplasmic reticulum (putative) - cytoplasmic vesicle (putative) - cell junction, synapse - associated with perikaryal rough endoplasmic reticulum as well as cytoplasmic large granular vesicles at synapses (putative) Expression: - abundantly expressed in subthalamic nucleus [4] - no expression in other brain regions tested [4] (hypothalamus was not tested) [4] - not expressed in heart, placenta, lung, liver, skeletal muscle, kidney or pancreas - expressed in hypothalamus a) concentrated in perifornical nucleus & dorsal, lateral & posterior hypothalamus b) dense localization in monoaminergic neurons - expressed in pons [1] Pathology: - deficiency of hypocretins (low CSF levels) or defect in hypocretins may result in narcolepsy - hypocretins/ orexins are absent &/or greatly diminished in the brain & CSF of most patients with narcolepsy - higher CSF orexin levels possible linked to sleep disorder in patients with Alzheimer's disease Pharmacology: - orexin receptor antagonist suvorexant FDA-approved to treat insomnia [6] Notes: - Orexin from the Greek orexis meaning appetite. orexin-A = hypocretin-1; orexin-B = hypocretin-2

Related

hypocretin receptor; orexin receptor (Hcrtr)

General

neurotransmitter peptide

Properties

SIZE: entity length = 131 aa MW = 13 kD COMPARTMENT: cytoplasm endoplasmic reticulum MOTIF: signal sequence {1-33} cysteine residue {C39} MODIFICATION: cysteine residue {C45} cysteine residue {C40} MODIFICATION: cysteine residue {C47} cysteine residue {C45} MODIFICATION: cysteine residue {C39} cysteine residue {C47} MODIFICATION: cysteine residue {C40}

Database Correlations

OMIM correlations MORBIDMAP 602358 UniProt O43612 Pfam PF02072 Entrez Gene 3060 Kegg hsa:3060

References

  1. Journal Watch 20(21):170, 2000
  2. Peyron C et al A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med 6:991,2000 PMID: 10973318
  3. Sakurai T et al Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573, 1998 PMID: 9491897
  4. UniProt :accession O43612
  5. Protein Spotlight; qui dort dine - Issue 15 of October 2001 http://web.expasy.org/spotlight/back_issues/sptlt015.shtml
  6. FDA News Release. August 13, 2014 FDA approves new type of sleep drug, Belsomra http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm
  7. Liguori C et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014 Oct 13; PMID: 25322206 - Ferini-Strambi L. Possible role of orexin in the pathogenesis of Alzheimer disease. JAMA Neurol 2014 Oct 13 PMID: 25317720