View source for Orexin

{{Refimprove|date=November 2009}}
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{{Pfam_box
| Symbol = Orexin
| Name = Prepro-orexin
| image = 1R02 crystallography.png
| width =
| caption = Solution phase [[NMR]] structure of orexin A based on the [[Protein Data Bank|PDB]] coordinates {{PDB2|1R02}}.
| Pfam = PF02072
| InterPro = IPR001704
| SMART=
| Prosite =
| SCOP = 1cq0
| TCDB =
| OPM family =154
| OPM protein = 1wso
| PDB= {{PDB3|1cq0}}A:71-97 {{PDB3|1wso}}A:35-66 {{PDB3|1r02}}A:34-66 {{PDB3|1uvq}}C:1-13
}}
{{FixBunching|mid}}
{{protein
|Name=hypocretin (orexin) neuropeptide precursor
|caption=Solution phase NMR structure of orexin B based on the [[Protein Data Bank|PDB]] coordinates {{PDB2|1CQ0}}.
|image=1CQ0 crystallography.png
|width=
|HGNCid=4847
|Symbol=HCRT
|AltSymbols=PPOX, OX
|EntrezGene=3060
|OMIM=602358
|RefSeq=NM_001524
|UniProt=O43612
|PDB=
|ECnumber=
|Chromosome=17
|Arm=q
|Band=21
|LocusSupplementaryData=
}}
{{FixBunching|end}}
'''Orexins''', also called '''hypocretins''', are the common names given to a pair of excitatory [[neuropeptide]] [[hormone]]s that were simultaneously discovered by two groups of researchers in [[rat]] brains.<ref name="pmid9491897">{{cite journal | author = 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 | title = Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior | journal = Cell | volume = 92 | issue = 4 | pages = 573–85 | year = 1998 | pmid = 9491897 | doi = 10.1016/S0092-8674(00)80949-6 }}</ref><ref name="pmid9419374">{{cite journal | author = 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 | title = The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 1 | pages = 322–7 | year = 1998 | pmid = 9419374 | doi = 10.1073/pnas.95.1.322 | pmc = 18213 }}</ref>

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 two [[G-protein coupled receptor|G-protein coupled]] [[orexin receptor]]s, [[Hypocretin (orexin) receptor 1|OX<sub>1</sub>]] and [[Hypocretin (orexin) receptor 2|OX<sub>2</sub>]], with Orexin-A binding to both OX<sub>1</sub> and OX<sub>2</sub> with approximately equal affinity while Orexin-B binds mainly to OX<sub>2</sub> and is 5 times less potent at OX<sub>1</sub>.<ref name="pmid14691055">{{cite journal | author = Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ | title = Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor | journal = Br. J. Pharmacol. | volume = 141 | issue = 2 | pages = 340–6 | year = 2004 | month = January | pmid = 14691055 | pmc = 1574197 | doi = 10.1038/sj.bjp.0705610 | url = | issn = }}</ref>

The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates.{{cn|date=November 2009}}

== Function ==

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 (psychological)|energy]] expenditure.

=== Wakefulness ===

Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin/hypocretin system is to integrate metabolic, circadian and [[sleep debt]] influences to determine whether an animal should be asleep or awake and active. Orexin/hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the [[dopamine]], [[norepinephrine]], [[histamine]] and [[acetylcholine]] systems<ref name="pmid9614245">{{cite journal | author = Sherin JE, Elmquist JK, Torrealba F, Saper CB | title = Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat | journal = J. Neurosci. | volume = 18 | issue = 12 | pages = 4705–21 | year = 1998 | month = June | pmid = 9614245 | doi = | url = http://www.jneurosci.org/cgi/content/full/18/12/4705 | issn = }}</ref><ref name="pmid12040064">{{cite journal | author = Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB | title = Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep | journal = J. Neurosci. | volume = 22 | issue = 11 | pages = 4568–76 | year = 2002 | month = June | pmid = 12040064 | doi = | url = http://www.jneurosci.org/cgi/content/full/22/11/4568 | issn = }}</ref> and appear to play an important role in stabilizing wakefulness and sleep.

The discovery that an orexin/hypocretin receptor mutation causes the [[sleep disorder]] canine [[narcolepsy]]<ref name="pmid10458611">{{cite journal | doi = 10.1016/S0092-8674(00)81965-0 | author = Lin L, Faraco J, et. al. | title = The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. | journal = Cell | volume = 98 | issue = 3 | pages = 365–376 | year = 1999 | pmid = 10458611 }}</ref> in [[Doberman_Pinscher|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.<ref name="pmid10481909">{{cite journal | doi = 10.1016/S0092-8674(00)81973-X | author = Chemelli RM, Willie JT, et. al. | title = Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. | journal = Cell | volume = 98 | issue = 4 | pages = 437–451 | year = 1999 | pmid = 10481909 }}</ref> 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.<ref name="pmid15254084">{{cite journal | author = Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE | title = Behavioral state instability in orexin knock-out mice | journal = J. Neurosci. | volume = 24 | issue = 28 | pages = 6291–300 | year = 2004 | month = July | pmid = 15254084 | doi = 10.1523/JNEUROSCI.0586-04.2004 | url =  }}</ref> 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/hypocretin have narcolepsy, while animals and people lacking the orexin/hypocretin neuropeptide itself also have narcolepsy.

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 [[Body mass index|BMI]], as would be expected if orexin/hypocretin were primarily an appetite stimulating peptide.  Another indication that deficits of orexin/hypocretin 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.<ref>{{cite web | url = http://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation | title = Snorting a Brain Chemical Could Replace Sleep |accessdate = 2008-02-05 | author= Alexis Madriga | date= 2007-12-28 | publisher = Wired News, Condé Nast  }}</ref><ref name="pmid18160631">{{cite journal | author = Deadwyler SA, Porrino L, Siegel JM, Hampson RE | title = Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates | journal = J. Neurosci. | volume = 27 | issue = 52 | pages = 14239–47 | year = 2007 | pmid = 18160631 | doi = 10.1523/JNEUROSCI.3878-07.2007 }}</ref> 

In humans, narcolepsy is associated with a specific variant of the [[human leukocyte antigen]] (HLA) complex.<ref name="pmid10984567">{{cite journal | author = Klein J, Sato A | title = The HLA system. Second of two parts | journal = N. Engl. J. Med. | volume = 343 | issue = 11 | pages = 782–6 | year = 2000 | month = September | pmid = 10984567 | doi = 10.1056/NEJM200009143431106| url = | issn = }}</ref> Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic [[mutation]] in the [[T cell|T-cell]] [[T cell receptor|receptor]] alpha locus.<ref name="pmid19412176">{{cite journal | author = Hallmayer J, Faraco J, Lin L, ''et al.'' | title = Narcolepsy is strongly associated with the T-cell receptor alpha locus | journal = Nat. Genet. | volume = 41 | issue = 6 | pages = 708–11 | year = 2009 | month = June | pmid = 19412176 | doi = 10.1038/ng.372 | url = | issn = | pmc = 2803042 }}</ref> In conjunction, these genetic anomalies cause the autoimmune system to attack and kill the critical hypocretin neurons. Hence the absence of hypocretin-producing [[neuron]]s in narcoleptic humans may be the result of an [[autoimmunity|autoimmune]] disorder.<ref name="url_eurekalert">{{cite web | url = http://www.eurekalert.org/pub_releases/2009-05/sumc-nia042809.php | title = Narcolepsy is an autoimmune disorder, Stanford researcher says | author = | authorlink = | coauthors = | date = 2009-05-03| format = | work = EurekAlert | publisher = American Association for the Advancement of Science | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-05-31}}</ref>

=== Wakefulness, Amyloid beta, and Alzheimer's disease ===

A link between orexin and [[Alzheimer's disease]] has been recently suggested.<ref name="kang">{{cite journal | title = Amyloid-{beta} Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle | author = J. E. Kang, M. M. Lim, R. J. Bateman, J. J. Lee, L. P. Smyth, J. R. Cirrito, N. Fujiki, S. Nishino and D. M. Holtzman | journal = Science | volume = | page=  | doi =  10.1126/science.1180962  | year = 2009}}</ref> The enigmatic protein [[amyloid beta]] builds up over time in the brain and is correlated with Alzheimer's disease. The recent research shows that amyloid beta expression rises during the day and falls during the night, and that this is controlled by orexin.<ref name="kang" /> Sleep deprivation is suggested to lead to amyloid beta plaque development.<ref name="kang" /> It is suggested that drugs that block orexin receptors could be used to modulate amyloid beta build-up.<ref name="kang" /> This research also suggests that maintaining proper lengths of sleep and wake periods could prevent Alzheimer's disease, assuming that 1) amyloid beta is the cause of Alzheimer's disease and 2) that sleep-wake cycling rather than some other cause is what leads to the amyloid beta build-up in the brains of people with Alzheimer's disease—two facts that have not been proven.

=== 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. 

Hypocretin-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/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.

=== Pharmacologic potential ===

The research on orexin/hypocretin is still in an early phase, although many scientists believe that orexin/hypocretin-based drugs could help [[narcolepsy|narcoleptics]] and increase alertness in the brain without the side effects of [[amfetamine|amphetamines]].

Preliminary research has been conducted that shows potential for orexin blockers in the treatment of [[alcoholism]]. [[Brown rat|Lab rat]]s given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.<ref>{{cite news | url = http://www.worldcampaign.net/forum/view.php?id=1707 | author = Helen Puttick | title = Hope in fight against alcoholism | date = 2006-12-26 | publisher = [[The Herald (Glasgow)|The Herald]] }}</ref><ref name="pmid16751790">{{cite journal | author = Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B | title = The orexin system regulates alcohol-seeking in rats | journal = Br. J. Pharmacol. | volume = 148 | issue = 6 | pages = 752–9 | year = 2006 | pmid = 16751790 | doi = 10.1038/sj.bjp.0706789 | pmc = 1617074 }}</ref>

A study has 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.<ref name="pmid15683135">{{cite journal | author = Arias-Carrión O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colín R, Shiromani PJ | title = Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results | journal = Sleep | volume = 27 | issue = 8 | pages = 1465–70 | year = 2004 | pmid = 15683135 | doi = | issn = | url = http://www.journalsleep.org/Articles/270802.pdf | format = | pmc = 1201562 }}</ref>

Because hypocretin-1 receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats. By blocking the hypocretin-1 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 hypocretin-1 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 hypocretin-1 receptors. It has been reported that smokers who sustained damage to the insula lost the desire to smoke.<ref name="urlBlocking A Neuropeptide Receptor Decreases Nicotine Addiction">{{cite web | url = http://www.sciencedaily.com/releases/2008/11/081124174851.htm | title = Blocking A Neuropeptide Receptor Decreases Nicotine Addiction | author = | authorlink = | coauthors = | date = 2008-12-01 | work = | publisher = ScienceDaily LLC | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-02-11}}</ref>

== 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.<ref name="pmid8710940">{{cite journal | doi = 10.1073/pnas.93.16.8733 | author = Gautvik KM, de Lecea L, et. al. | title = Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. | journal = PNAS | volume = 93 | issue = 16 | pages = 8733–8738 | year = 1996 | pmid = 8710940 | pmc = 38742 }}</ref> Two years later they would identify the two genetic products of clone 35 as the hypocretins.

[[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 OX<sub>1</sub>R and OX<sub>2</sub>R.<ref name="pmid9491897"/>

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., ''hypo''thalamic se''cretin''). This is the same group that first identified clone 35 two years earlier.<ref name="pmid9419374"/><ref name="pmid8710940"/>

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., hypocretin 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 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]] is under development by [[GlaxoSmithKline]] for sleep disorders and is a non-selective orexin receptor antagonist. Another OX<sub>1</sub> and OX<sub>2</sub> 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 OX<sub>1</sub> antagonist
* [[SB-408,124]] - selective OX<sub>1</sub> antagonist
* [[TCS-OX2-29]] - selective OX<sub>2</sub> antagonist

== Interaction with other neurotransmitter systems ==

Orexinergic neurons have been shown to be sensitive to inputs from Group III [[metabotropic glutamate receptors]],<ref name="pmid15044540">{{cite journal | author = Acuna-Goycolea C, Li Y, Van Den Pol AN | title = Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons | journal = J. Neurosci. | volume = 24 | issue = 12 | pages = 3013–22 | year = 2004 | month = March | pmid = 15044540 | doi = 10.1523/JNEUROSCI.5416-03.2004 | url = | issn = }}</ref> [[adenosine A1 receptor]]s,<ref name="pmid17093123">{{cite journal | author = Liu ZW, Gao XB | title = Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect | journal = J. Neurophysiol. | volume = 97 | issue = 1 | pages = 837–48 | year = 2007 | month = January | pmid = 17093123 | pmc = 1783688 | doi = 10.1152/jn.00873.2006 | url = | issn = }}</ref> [[Muscarinic acetylcholine receptor M3|muscarinic M3 receptors]],<ref name="pmid18344611">{{cite journal | author = Ohno K, Hondo M, Sakurai T | title = Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice | journal = J. Pharmacol. Sci. | volume = 106 | issue = 3 | pages = 485–91 | year = 2008 | month = March | pmid = 18344611 | doi = 10.1254/jphs.FP0071986| url = http://joi.jlc.jst.go.jp/JST.JSTAGE/jphs/FP0071986?from=PubMed | issn = | format = {{dead link|date=May 2010}} }}</ref> serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptors]],<ref name="pmid15306649">{{cite journal | author = Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T | title = Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor | journal = J. Neurosci. | volume = 24 | issue = 32 | pages = 7159–66 | year = 2004 | month = August | pmid = 15306649 | doi = 10.1523/JNEUROSCI.1027-04.2004 | url = | issn = }}</ref> [[neuropeptide Y]] receptors,<ref name="pmid15470140">{{cite journal | author = Fu LY, Acuna-Goycolea C, van den Pol AN | title = Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system | journal = J. Neurosci. | volume = 24 | issue = 40 | pages = 8741–51 | year = 2004 | month = October | pmid = 15470140 | doi = 10.1523/JNEUROSCI.2268-04.2004 | url = | issn = }}</ref> [[cholecystokinin A receptor]]s,<ref name="pmid16093397">{{cite journal | author = Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = J. Neurosci. | volume = 25 | issue = 32 | pages = 7459–69 | year = 2005 | month = August | pmid = 16093397 | doi = 10.1523/JNEUROSCI.1193-05.2005 | url = | issn = }}</ref> and [[catecholamines]],<ref name="pmid15634779">{{cite journal | author = Li Y, van den Pol AN | title = Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons | journal = J. Neurosci. | volume = 25 | issue = 1 | pages = 173–83 | year = 2005 | month = January | pmid = 15634779 | doi = 10.1523/JNEUROSCI.4015-04.2005 | url = | issn = }}</ref><ref name="pmid16611835">{{cite journal | author = Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T | title = Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner | journal = J. Neurophysiol. | volume = 96 | issue = 1 | pages = 284–98 | year = 2006 | month = July | pmid = 16611835 | doi = 10.1152/jn.01361.2005 | url = | issn = }}</ref> as well as to [[ghrelin]], [[leptin]], and [[glucose]].<ref name="pmid17910982">{{cite journal | author = Ohno K, Sakurai T | title = Orexin neuronal circuitry: role in the regulation of sleep and wakefulness | journal = Front Neuroendocrinol | volume = 29 | issue = 1 | pages = 70–87 | year = 2008 | month = January | pmid = 17910982 | doi = 10.1016/j.yfrne.2007.08.001 | url = | issn = }}</ref> Orexinergic neurons themselves regulate release of [[acetylcholine]],<ref name="pmid14622212">{{cite journal | author = Bernard R, Lydic R, Baghdoyan HA | title = Hypocretin-1 causes G protein activation and increases ACh release in rat pons | journal = Eur. J. Neurosci. | volume = 18 | issue = 7 | pages = 1775–85 | year = 2003 | month = October | pmid = 14622212 | doi = 10.1046/j.1460-9568.2003.02905.x | url = | issn = }}</ref><ref name="pmid17928158">{{cite journal | author = Frederick-Duus D, Guyton MF, Fadel J | title = Food-elicited increases in cortical acetylcholine release require orexin transmission | journal = Neuroscience | volume = 149 | issue = 3 | pages = 499–507 | year = 2007 | month = November | pmid = 17928158 | doi = 10.1016/j.neuroscience.2007.07.061 | url = | issn = }}</ref> [[serotonin]] and [[noradrenaline]],<ref name="pmid15111023">{{cite journal | author = Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH | title = Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus | journal = Neuropharmacology | volume = 46 | issue = 8 | pages = 1168–76 | year = 2004 | month = June | pmid = 15111023 | doi = 10.1016/j.neuropharm.2004.02.014 | url = | issn = }}</ref> 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_alpha_subunit|Gq-protein]]-coupled receptors signaling through [[phospholipase C]] (PLC)- and calcium-dependent as well as calciumindependent transduction pathways. These include activation of electrogenic [[Sodium-calcium_exchanger|sodium-calcium exchangers]] (NCX) and a non-specific cationic conductance, likely channels of the [[TRPC|transient receptor potential canonical]]-(TRPC) type activation of [[L-type_calcium_channel|L-type voltage-dependent calcium channels]], closure of [[G protein-coupled inwardly-rectifying potassium channel|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.<ref name="pmid16687280">{{cite journal | author = Selbach O, Haas HL | title = Hypocretins: the timing of sleep and waking | journal = Chronobiology International | volume = 23 | issue = 1-2 | pages = 63–70 | year = 2006 | pmid = 16687280 | doi = 10.1080/07420520500545961 | url = | issn = }}</ref>

==See also==
* [[Leptin]]

==References==
{{Reflist|2}}

==External links==
* {{MeshName|orexins}}

{{Neuropeptides}}
{{Neurotransmitters}}

[[Category:Endocrinology]]
[[Category:Peptide hormones]]
[[Category:Neuropeptides]]
[[Category:Orexin antagonists]]

[[ca:Hipocretina]]
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[[pl:Hipokretyna]]
[[pt:Hipocretina]]
[[ru:Орексин]]
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[[Category:2Fix]]