関: orexin、orexin A、orexin B

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/25 16:37:36」(JST)

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Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite.^[1] The most common form of narcolepsy, in which the sufferer briefly loses muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.^[2]

The brain contains very few cells that produce orexin; in a human brain, about 10,000 to 20,000 neurons^[2] in the hypothalamus.^[1] However, the axons from these neurons extend throughout the entire brain and spinal cord,^[3] where there are also receptors for orexin.

Orexin was discovered in 1998 almost simultaneously by two independent groups of rat-brain researchers.^[4]^[5] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, a hormone found in the gut.^[2] The scientific community has not yet settled on a consensus for which word to use.

Isoforms

There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptide hormones with approximately 50% sequence identity, produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Studies suggest that orexin-A may be of greater biological importance than orexin-B.^{[citation needed]} 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 two G-protein coupled orexin receptors, OX₁ and OX₂, with orexin-A binding to both OX₁ and OX₂ with approximately equal affinity while orexin-B binds mainly to OX₂ and is 5 times less potent as OX₁.^[6]

The orexins are strongly conserved peptides, found in all major classes of vertebrates.^{[citation needed]}

Function

The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. In addition, it stimulates wakefulness and energy expenditure.

Brown fat activation

Obesity in orexin knockout mice is a result of inability of brown preadipocytes to differentiate into brown adipose tissue (BAT), which in turn reduces BAT thermogenesis. BAT differentiation can be restored in these knockout mice through injections of orexin. Deficiency in orexin has also been linked to narcolepsy, a sleep disorder. Furthermore narcoleptic people are more likely to be obese. Hence obesity in narcoleptic patients may be due to orexin deficiency leading to impaired thermogenesis and energy expenditure.^[7]

Wakefulness

Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep or awake and active. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems^[8]^[9] and appear to play an important role in stabilizing wakefulness and sleep.

The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy^[10] in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.^[11] 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.^[12] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.

Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin 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.^[13]^[14]

In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.^[15] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.^[16] In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.^[17]

Food intake

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.

Orexin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.^{[citation needed]} 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. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.^[18]

Pharmacologic potential

Many scientists believe that orexin-based drugs could increase alertness in the brain without the side effects of substituted amphetamines.

Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, suvorexant, fell asleep faster and slept an hour longer. Suvorexant was tested for three months on over a thousand patients in a phase III trial. Survorexant has undergone three phase III trials and was approved on August 13, 2014 by the US Food and Drug Administration (FDA) after being denied approval the year before.^[19] It will be made available as "Belsomra".

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.^[20]^[21]

A study has reported that transplantation of orexin 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.^[22]

Because orexin-A receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats. By blocking the orexin-A receptor with low doses of the selective antagonist SB-334,867, nicotine self-administration decreased and also the motivation to seek and obtain the drug. The study showed that blocking of receptors in the insula decreased self-administration, but not blocking of receptors in the adjacent somatosensory cortex. The greatest decrease in self-administration was found when blocking all orexin-A receptors in the brain as a whole. A rationale for this study was the fact that the insula has been implicated in regulating feelings of craving. The insula contains orexin-A receptors. It has been reported that smokers who sustained damage to the insula lost the desire to smoke.^[23]

Lipid metabolism

Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes.^[24] The link between OXA and the lipid metabolism is new and currently under more research.

Obesity in orexin-knockout mice is associated with impaired brown adipose tissue thermogenesis.^[7]

Mood

High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.^[25] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression. Likewise, it helps explain the incidence of depression associated with narcolepsy.

History and nomenclature

In 1996, Gautvik, de Lecea, and colleagues reported the discovery of several genes in the rat brain, including one they dubbed "clone 35." Their work showed that clone 35 expression was limited to the lateral hypothalamus.^[26]

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. In their 1998 paper (with authorship attributed to Sakurai and colleagues) describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed OX₁R and OX₂R.^[4]

In 1998, Luis de Lecea, 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 structural similarity to the hormone secretin (i.e., hypothalamic secretin). This is the same group that first identified clone 35 two years earlier.^[5]^[26] De Lecea and colleagues were originally in search of novel genes expressed in the hypothalamus. To do this, they extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it under electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, so de Lecea decided to name the two forms of peptides hypocretin-1 and hypocretin-2.^[27] These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemmistry tactics revealed the various projections this area truly had to other parts of the brain. A majority of these projections reached the limbic system and structures associated with it (including the amygdala, septum, and basal forebrain area).

The name of this family of peptides is currently an unsettled issue. 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., orexin induced subjects eat more because they are awake more), though this issue is also unsettled, 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. Both "orexin" and "hypocretin" will likely continue to appear in published works until a preferred name has been accepted by the scientific community.

Selective ligands

Several drugs^[28] 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 and tested on monkeys. Several non-peptide antagonists are in development however; SB-649,868 by GlaxoSmithKline for sleep disorders is a non-selective orexin receptor antagonist. Another dual orexin antagonist, almorexant(ACT-078573) by Actelion, was abandoned because of side effects. A third entry is Merck's suvorexant (Belsomra),^[29] which has recently been approved for use. A new antagonist compound, ACT-462206, was recently studied in humans.^[30]

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
SB-408,124 – selective OX₁ antagonist
TCS-OX2-29 – selective OX₂ antagonist
EMPA(drug) (N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) – selective OX₂ antagonist

Signal transduction

Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,^[31] adenosine A₁ receptors,^[32] muscarinic M₃ receptors,^[33] serotonin 5-HT_1A receptors,^[34] neuropeptide Y receptors,^[35] cholecystokinin A receptors,^[36] and catecholamines,^[37]^[38] as well as to ghrelin, leptin, and glucose.^[39] Orexinergic neurons themselves regulate release of acetylcholine,^[40]^[41] serotonin and noradrenaline,^[42] so despite the relatively small number of orexinergic neurons compared to other neurotransmitter systems in the brain, this system plays a key regulatory role and extensive research will be required to unravel the details. Orexins act on Gq-protein-coupled receptors signaling through phospholipase C (PLC) and calcium-dependent as well as calcium-independent transduction pathways. These include activation of electrogenic sodium-calcium exchangers (NCX) and a non-specific cationic conductance, likely channels of the transient receptor potential canonical-(TRPC) type activation of L-type voltage-dependent calcium channels, closure of G-protein-activated inward rectifier potassium channels (GIRK), and activation of protein kinases, including protein kinase C (PKC), protein kinase A (PKA), and mitogen-associated protein kinase, also called mitogen-activated protein kinase (MAPK). Postsynaptic actions of orexins on their numerous neuronal targets throughout the CNS are almost entirely excitatory.^[43]

References

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^ ^a ^b ^c Stanford Center for Narcolepsy FAQ (retrieved 27-Mar-2012)
^ Marcus JN, Elmquist JK (2006). "3. Orexin Projections and Localization of Orexin Receptors". In Nishino S, Sakurai T. The Orexin/Hypocretin System: Physiology and Pathophysiology. Springer. p. 195. ISBN 9781592599509.
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^ http://journal.frontiersin.org/Journal/10.3389/fendo.2013.00018/full
^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm
^ Helen Puttick (2006-12-26). "Hope in fight against alcoholism". The Herald.
^ 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. doi:10.1038/sj.bjp.0706789. PMC 1617074. PMID 16751790.
^ 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" (PDF). Sleep 27 (8): 1465–70. PMC 1201562. PMID 15683135.
^ "Blocking A Neuropeptide Receptor Decreases Nicotine Addiction". ScienceDaily LLC. 2008-12-01. Retrieved 2009-02-11.
^ Skrzypski M, Le TT, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D, Kolodziejski PA, Sassek M, Arafat A, Wiedenmann B, Nowak KW, Strowski MZ (July 2011). "Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes". Diabetologia 5 (47): 1841–52. doi:10.1007/s00125-011-2152-2. PMID 21505958.
^ Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KÆ, Lapierre JL, Siegel JM (2013). "Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction". Nature Communications 4: 1547. doi:10.1038/ncomms2461. PMC 3595130. PMID 23462990. Lay summary – Science Daily.
^ ^a ^b Gautvik KM, de Lecea L et al. (1996). "Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction". PNAS 93 (16): 8733–8738. doi:10.1073/pnas.93.16.8733. PMC 38742. PMID 8710940.
^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279673/
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^ Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ (2011). "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder". Organic Process Research & Development 15 (2): 367–375. doi:10.1021/op1002853.
^ "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant.". J Clin Pharmacol. 54: 979–86. Sep 2014. doi:10.1002/jcph.297. PMID 24691844.
^ Acuna-Goycolea C, Li Y, Van Den Pol AN (March 2004). "Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons". J. Neurosci. 24 (12): 3013–22. doi:10.1523/JNEUROSCI.5416-03.2004. PMID 15044540.
^ Liu ZW, Gao XB (January 2007). "Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect". J. Neurophysiol. 97 (1): 837–48. doi:10.1152/jn.00873.2006. PMC 1783688. PMID 17093123.
^ Ohno K, Hondo M, Sakurai T (March 2008). "Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice". J. Pharmacol. Sci. 106 (3): 485–91. doi:10.1254/jphs.FP0071986. PMID 18344611. ^{[dead link]}
^ Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T (August 2004). "Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor". J. Neurosci. 24 (32): 7159–66. doi:10.1523/JNEUROSCI.1027-04.2004. PMID 15306649.
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^ Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T (August 2005). "Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor". J. Neurosci. 25 (32): 7459–69. doi:10.1523/JNEUROSCI.1193-05.2005. PMID 16093397.
^ Li Y, van den Pol AN (January 2005). "Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons". J. Neurosci. 25 (1): 173–83. doi:10.1523/JNEUROSCI.4015-04.2005. PMID 15634779.
^ Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T (July 2006). "Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner". J. Neurophysiol. 96 (1): 284–98. doi:10.1152/jn.01361.2005. PMID 16611835.
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External links

orexins at the US National Library of Medicine Medical Subject Headings (MeSH)
http://www.sleepfoundation.org/article/compare-different-sleep-aids
http://www.sleepfoundation.org/alert/drug-may-offer-new-approach-treating-insomnia
http://www.sleepfoundation.org/article/orexin-receptor-antagonists-new-class-sleeping-pill

UpToDate Contents

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1. Clinical features and diagnosis of narcolepsy in adults
2. 不眠症の治療 treatment of insomnia
3. 睡眠の質および睡眠の構造に対する薬剤の効果 the effects of medications on sleep quality and sleep architecture
4. Narcolepsy in children
5. 肥満の病因 pathogenesis of obesity

English Journal

Orexin-A increases the firing activity of hippocampal CA1 neurons through orexin-1 receptors.

Chen XY1, Chen L2, Du YF1.
Journal of neuroscience research.J Neurosci Res.2017 Jul;95(7):1415-1426. doi: 10.1002/jnr.23975. Epub 2016 Oct 31.
PMID 27796054

A review of the role of orexin system in pain modulation.

Razavi BM1, Hosseinzadeh H2.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.Biomed Pharmacother.2017 Jun;90:187-193. doi: 10.1016/j.biopha.2017.03.053. Epub 2017 Mar 27.
PMID 28360013

Localization of orexin B and receptor 2 for orexins in testicular cytotypes of the camelid alpaca (Vicugna pacos).

Liguori G1, Squillacioti C1, Assisi L2, Mirabella N1, Langella E3, Costagliola A1, Vittoria A1.
Reproduction in domestic animals = Zuchthygiene.Reprod Domest Anim.2017 Jun;52(3):452-458. doi: 10.1111/rda.12931. Epub 2017 Feb 8.
PMID 28181310

Japanese Journal

Activation of Bombesin receptor subtype-3 influences activity of orexin neurons by both direct and indirect pathways

Furutani Naoki,Hondo Mari,Tsujino Natsuko,Sakurai Takeshi
Journal of Molecular Neuroscience 42(1), 106-111, 2010-09-00
… The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2), produced in lateral hypothalamic neurons, are critical regulators of feeding behavior, the reward system, and sleep/wake states. …
NAID 120002384286

Niemann-Pick Disease Type C : Cataplexy and Hypocretin in Cerebrospinal Fluid

OYAMA KATSUYUKI,TAKAHASHI TSUTOMU,SHOJI YUTAKA,OYAMADA MIKA,NOGUCHI ATSUKO,TAMURA HIROAKI,TAKADA GORO,KANBAYASHI TAKASHI
THE TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 209(3), 263-267, 2006-07-01
NAID 10019253788

Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity

MARTINS PJ
Regul Pept 117(3), 155-158, 2004
NAID 30005572441

Related Pictures

★リンクテーブル★

リンク元	「ハイポクレチン-1」「orexin A」「orexin B」「ヒポクレチン-1」

「ハイポクレチン-1」

orexin (hypocretin) neuropeptide precursor
	Solution phase NMR structure of orexin B based on the PDB coordinates 1CQ0.
Identifiers
Symbol	HCRT
Alt. symbols	PPOX, OX
Entrez	3060
HUGO	4847
OMIM	602358
RefSeq	NM_001524
UniProt	O43612
Other data
Locus	Chr. 17 q21

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Prepro-orexin
	Solution phase NMR structure of orexin A based on the PDB coordinates 1R02.
Identifiers
Symbol	Orexin
Pfam	PF02072
InterPro	IPR001704
SCOP	1cq0
SUPERFAMILY	1cq0
OPM superfamily	154
OPM protein	1wso
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

　　[★]

英: hypocretin-1
関: オレキシン、ヒ・クレチン-1、オレキシンA、オレキシンB

「orexin A」

　　[★]

オレキシンA

関: hypocretin-1、orexin、orexin B

「orexin B」

　　[★]

オレキシンB

関: hypocretin-1、orexin、orexin A

「ヒポクレチン-1」

　　[★]

英: hypocretin-1
関: ハイ・クレチン-1

[Davis-1] Davis JF, Choi DL, Benoit SC (2011). "24. Orexigenic Hypothalamic Peptides Behavior and Feeding - 24.5 Orexin". In Preedy VR, Watson RR, Martin CR. Handbook of Behavior, Food and Nutrition. Springer. pp. 361–2. ISBN 9780387922713.

[Stanford-2] Stanford Center for Narcolepsy FAQ (retrieved 27-Mar-2012)

[Marcus-3] Marcus JN, Elmquist JK (2006). "3. Orexin Projections and Localization of Orexin Receptors". In Nishino S, Sakurai T. The Orexin/Hypocretin System: Physiology and Pathophysiology. Springer. p. 195. ISBN 9781592599509.

[pmid9491897-4] 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. doi:10.1016/S0092-8674(00)80949-6. PMID 9491897.

[pmid9419374-5] 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. doi:10.1073/pnas.95.1.322. PMC 18213. PMID 9419374.

[pmid14691055-6] Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "Characterisation of the binding of 3H-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor". Br. J. Pharmacol. 141 (2): 340–6. doi:10.1038/sj.bjp.0705610. PMC 1574197. PMID 14691055.

[pmid21982708-7] Sellayah D, Bharaj P, Sikder D (October 2011). "Orexin is required for brown adipose tissue development, differentiation, and function". Cell Metab. 14 (4): 478–90. doi:10.1016/j.cmet.2011.08.010. PMID 21982708. Lay summary – ScienceDaily.

[pmid9614245-8] Sherin JE, Elmquist JK, Torrealba F, Saper CB (June 1998). "Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat". The Journal of Neuroscience 18 (12): 4705–21. PMID 9614245.

[pmid12040064-9] Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB (June 2002). "Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep". J. Neurosci. 22 (11): 4568–76. PMID 12040064.

[pmid10458611-10] Lin L, Faraco J et al. (1999). "The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene". Cell 98 (3): 365–376. doi:10.1016/S0092-8674(00)81965-0. PMID 10458611.

[pmid10481909-11] Chemelli RM, Willie JT et al. (1999). "Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation". Cell 98 (4): 437–451. doi:10.1016/S0092-8674(00)81973-X. PMID 10481909.

[pmid15254084-12] 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. doi:10.1523/JNEUROSCI.0586-04.2004. PMID 15254084.

[13] Alexis Madrigal (2007-12-28). "Snorting a Brain Chemical Could Replace Sleep". Wired News, Condé Nast. Retrieved 2008-02-05.

[pmid18160631-14] 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. doi:10.1523/JNEUROSCI.3878-07.2007. PMID 18160631.

[pmid10984567-15] Klein J, Sato A (September 2000). "The HLA system. Second of two parts". N. Engl. J. Med. 343 (11): 782–6. doi:10.1056/NEJM200009143431106. PMID 10984567.

[pmid19412176-16] Hallmayer J, Faraco J, Lin L et al. (June 2009). "Narcolepsy is strongly associated with the TCR alpha locus". Nat. Genet. 41 (6): 708–11. doi:10.1038/ng.372. PMC 2803042. PMID 19412176.

[url_eurekalert-17] "Narcolepsy is an autoimmune disorder, Stanford researcher says". EurekAlert. American Association for the Advancement of Science. 2009-05-03. Retrieved 2009-05-31.

[18] ttp://journal.frontiersin.org/Journal/10.3389/fendo.2013.00018/full

[19] ttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm

[20] Helen Puttick (2006-12-26). "Hope in fight against alcoholism". The Herald.

[pmid16751790-21] 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. doi:10.1038/sj.bjp.0706789. PMC 1617074. PMID 16751790.

[pmid15683135-22] 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" (PDF). Sleep 27 (8): 1465–70. PMC 1201562. PMID 15683135.

[urlBlocking_A_Neuropeptide_Receptor_Decreases_Nicotine_Addiction-23] "Blocking A Neuropeptide Receptor Decreases Nicotine Addiction". ScienceDaily LLC. 2008-12-01. Retrieved 2009-02-11.

[24] Skrzypski M, Le TT, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D, Kolodziejski PA, Sassek M, Arafat A, Wiedenmann B, Nowak KW, Strowski MZ (July 2011). "Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes". Diabetologia 5 (47): 1841–52. doi:10.1007/s00125-011-2152-2. PMID 21505958.

[happiness-25] Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KÆ, Lapierre JL, Siegel JM (2013). "Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction". Nature Communications 4: 1547. doi:10.1038/ncomms2461. PMC 3595130. PMID 23462990. Lay summary – Science Daily.

[pmid8710940-26] Gautvik KM, de Lecea L et al. (1996). "Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction". PNAS 93 (16): 8733–8738. doi:10.1073/pnas.93.16.8733. PMC 38742. PMID 8710940.

[27] ttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279673/

[Heifetz_2012-28] Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, Hallett D, Manikowski DP, Pal S, Reifegerste R, Slack M, Law R (2012). "Study of Human Orexin-1 and -2 G-Protein-Coupled Receptors with Novel and Published Antagonists by Modeling, Molecular Dynamics Simulations, and Site-Directed Mutagenesis". Biochemistry 51 (15): 3178–3197. doi:10.1021/bi300136h.

[Baxter_2011-29] Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ (2011). "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder". Organic Process Research & Development 15 (2): 367–375. doi:10.1021/op1002853.

[30] "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant.". J Clin Pharmacol. 54: 979–86. Sep 2014. doi:10.1002/jcph.297. PMID 24691844.

[pmid15044540-31] Acuna-Goycolea C, Li Y, Van Den Pol AN (March 2004). "Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons". J. Neurosci. 24 (12): 3013–22. doi:10.1523/JNEUROSCI.5416-03.2004. PMID 15044540.

[pmid17093123-32] Liu ZW, Gao XB (January 2007). "Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect". J. Neurophysiol. 97 (1): 837–48. doi:10.1152/jn.00873.2006. PMC 1783688. PMID 17093123.

[pmid18344611-33] Ohno K, Hondo M, Sakurai T (March 2008). "Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice". J. Pharmacol. Sci. 106 (3): 485–91. doi:10.1254/jphs.FP0071986. PMID 18344611. ^{[dead link]}

[pmid15306649-34] Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T (August 2004). "Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor". J. Neurosci. 24 (32): 7159–66. doi:10.1523/JNEUROSCI.1027-04.2004. PMID 15306649.

[pmid15470140-35] Fu LY, Acuna-Goycolea C, van den Pol AN (October 2004). "Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system". J. Neurosci. 24 (40): 8741–51. doi:10.1523/JNEUROSCI.2268-04.2004. PMID 15470140.

[pmid16093397-36] Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T (August 2005). "Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor". J. Neurosci. 25 (32): 7459–69. doi:10.1523/JNEUROSCI.1193-05.2005. PMID 16093397.

[pmid15634779-37] Li Y, van den Pol AN (January 2005). "Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons". J. Neurosci. 25 (1): 173–83. doi:10.1523/JNEUROSCI.4015-04.2005. PMID 15634779.

[pmid16611835-38] Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T (July 2006). "Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner". J. Neurophysiol. 96 (1): 284–98. doi:10.1152/jn.01361.2005. PMID 16611835.

[pmid17910982-39] Ohno K, Sakurai T (January 2008). "Orexin neuronal circuitry: role in the regulation of sleep and wakefulness". Front Neuroendocrinol 29 (1): 70–87. doi:10.1016/j.yfrne.2007.08.001. PMID 17910982.

[pmid14622212-40] Bernard R, Lydic R, Baghdoyan HA (October 2003). "Hypocretin-1 causes G protein activation and increases ACh release in rat pons". Eur. J. Neurosci. 18 (7): 1775–85. doi:10.1046/j.1460-9568.2003.02905.x. PMID 14622212.

[pmid17928158-41] Frederick-Duus D, Guyton MF, Fadel J (November 2007). "Food-elicited increases in cortical acetylcholine release require orexin transmission". Neuroscience 149 (3): 499–507. doi:10.1016/j.neuroscience.2007.07.061. PMID 17928158.

[pmid15111023-42] Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH (June 2004). "Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus". Neuropharmacology 46 (8): 1168–76. doi:10.1016/j.neuropharm.2004.02.014. PMID 15111023.

[pmid16687280-43] Selbach O, Haas HL (2006). "Hypocretins: the timing of sleep and waking". Chronobiology International 23 (1–2): 63–70. doi:10.1080/07420520500545961. PMID 16687280.

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案内

hypocretin-1