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Prepro-orexin
1R02 crystallography.png
Solution phase NMR structure of orexin A based on the PDB coordinates 1R02.
Identifiers
Symbol Orexin
Pfam PF02072
InterPro IPR001704
SCOP 1cq0
OPM family 154
OPM protein 1wso
hypocretin (orexin) neuropeptide precursor
1CQ0 crystallography.png
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

Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains.[1][2]

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 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 at OX1.[3]

The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates.[citation needed]

Contents

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 expenditure.

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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[4][5] 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[6] 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.[7] 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.[8] 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 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.[9][10]

In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.[11] 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.[12] In conjunction, these genetic anomalies cause the autoimmune system to attack and kill the critical hypocretin neurons. Hence the absence of hypocretin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.[13]

Wakefulness, Amyloid beta, and Alzheimer's disease

A link between orexin and Alzheimer's disease has been recently suggested.[14] 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.[14] Sleep deprivation is suggested to lead to amyloid beta plaque development.[14] It is suggested that drugs that block orexin receptors could be used to modulate amyloid beta build-up.[14] 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 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.[15][16]

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.[17]

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.[18]

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.[19] 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 OX1R and OX2R.[1]

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.[2][19]

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 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.

Interaction with other neurotransmitter systems

Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,[20] adenosine A1 receptors,[21] muscarinic M3 receptors,[22] serotonin 5-HT1A receptors,[23] neuropeptide Y receptors,[24] cholecystokinin A receptors,[25] and catecholamines,[26][27] as well as to ghrelin, leptin, and glucose.[28] Orexinergic neurons themselves regulate release of acetylcholine,[29][30] serotonin and noradrenaline,[31] 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 calciumindependent 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.[32]

See also

References

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  29. ^ 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. 
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