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|hypocretin (orexin) neuropeptide precursor|
|Symbol(s):||HCRT PPOX, OX|
The two related peptides (Orexin-A and B, or hypocretin-1 and -2), with approximately 50% sequence identity, are produced by cleavage of a single precursor protein. Orexin-A/hypocretin-1 is 33 amino acid residues long and has two intrachain disulfide bonds, while Orexin-B/hypocretin-2 is a linear 28 amino acid residue peptide. Studies suggest that orexin A/hypocretin-1 may be of greater biological importance than orexin B/hypocretin-2. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. The orexin peptides bind to the orexin receptor, a G-protein coupled receptor.
The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates. The peptides are thought to have arisen early in vertebrate evolution.
The orexin/hypocretin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin A/hypocretin-1 increases food intake. In addition, it stimulates wakefulness and energy expenditure.
Orexin seems to promote wakefulness.
The discovery that orexin/hypocretin dysregulation causes the sleep disorder narcolepsy in mice subsequently indicated a major role for this system in sleep regulation. Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy (loss of muscle tone in response to strong, usually positive, emotions). Dogs that lack a functional receptor for orexin/hypocretin have narcolepsy, while animals and people lacking the orexin/hypocretin neuropeptide itself also have narcolepsy. Orexin/hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilizing wakefulness and sleep.
Recent studies indicate that a major role of the orexin/hypocretin system is to integrate metabolic, circadian and sleep debt influences to determine whether the animal should be asleep or awake and active. Central administration of orexin A/hypocretin-1 strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin A/hypocretin-1 transmission. The orexin/hypocretin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin/hypocretin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin/hypocretin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30-36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.
Recently, transgenic mice have been engineered to lack the gene for orexin. Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease.
Orexin increases the craving for food, and correlates with the function of the substances that promote its production.
Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.
Hypocretin-producing cells have recently been shown to be inhibited by leptin (by leptin receptors), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin/hypocretin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation. Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis.
The research on orexin/hypocretin is still in an early phase, although many scientists believe that orexin/hypocretin-based drugs could help narcoleptics and increase alertness in the brain without the side effects of amphetamines.
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism. Lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.
Finally, a recent study reported that transplantation of orexin/hypocretin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.
History and nomenclatureEdit
Masashi Yanagisawa and colleagues at the University of Texas Southwestern Medical Center at Dallas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these hormones. 
Luis DeLecea, Thomas Kilduff, and colleagues also reported discovery of these same peptides, dubbing them hypocretins to indicate that they are synthesized in the hypothalamus and to reflect their similarity to a class of hormones called incretins (i.e., hypothalamic incretin).
The name of this family of peptides is currently in dispute. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial (i.e., hypocretin induced subjects eat more because they are awake more), while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions, and that waking is one of the important factors that supports feeding behavior. The name "hyporexin" has been suggested as a compromise, but as of yet has not been commonly used. Both "orexin" and "hypocretin" will likely continue to appear in published works until a preferred name has been accepted by the scientific community.
Several drugs acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. No non-peptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray. Several non-peptide antagonists are in development however; SB-649,868 is under development by GlaxoSmithKline for sleep disorders and is an orexin receptor antagonist. Another OX1 and OX2 receptor antagonist (ACT-078573, almorexant) is a similar compound under development for primary insomnia by Actelion.
Most ligands acting on the orexin system so far are polypeptides modified from the endogenous agonists Orexin-A and Orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.
- SB-334,867 - selective OX1 antagonist, N-(2-Methyl-6-benzoxazolyl)-N"-1,5-naphthyridin-4-yl urea, CAS# 249889-64-3
- SB-408,124 - selective OX1 antagonist, orally active, N-(6,8-Difluoro-2-methyl-4-quinolinyl)-N'-[4-(dimethyla mino)phenyl]urea, CAS# 288150-92-5
- ↑ 1.0 1.1 Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 (4): 573–85.
- ↑ 2.0 2.1 de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A. 95 (1): 322–7.
- ↑ Siegel JM (1999). Narcolepsy: a key role for hypocretins (orexins). Cell 98 (4): 409–12.
- ↑ Alexis Madriga. Snorting a Brain Chemical Could Replace Sleep. Wired News, Condé Nast. URL accessed on 2008-02-05.
- ↑ Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007). Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J. Neurosci. 27 (52): 14239–47.
- ↑ Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE (July 2004). Behavioral state instability in orexin knock-out mice. J. Neurosci. 24 (28): 6291–300.
- ↑ includeonly>Helen Puttick. "Hope in fight against alcoholism", The Herald, 2006-12-26.
- ↑ Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006). The orexin system regulates alcohol-seeking in rats. Br. J. Pharmacol. 148 (6): 752–9.
- ↑ Arias-Carrión O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colín R, Shiromani PJ (2004). Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results. Sleep 27 (8): 1465–70.
Angiotensin - Bombesin/Neuromedin B - Calcitonin gene-related peptide - Carnosine - Delta sleep-inducing peptide - FMRFamide - Galanin - Gastrin releasing peptide - Kinins (Bradykinin, Tachykinins ) - Neuromedin (B, N, U) - Neuropeptide Y - Neurophysins - Neurotensin - Opioid peptide - Pancreatic polypeptide - Pituitary adenylate cyclase activating peptide
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