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.
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.
The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates.
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.
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 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 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. 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. 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.
In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex. 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. 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.
Wakefulness, Amyloid beta, and Alzheimer's disease
A link between orexin and
Alzheimer's disease has been recently suggested. 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.
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.
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.
Lipid Metabolism
Orexin-A (OXA) has been recently demonstrated to have direct effect on a part of the
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 inhibit
lipolysis and stimulates the secretion of
adiponectin. These effects are though to be mostly conferred via the
PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes. The link between OXA and the lipid metabolism is new and currently under more research.
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. 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. adenosine A1 receptors, muscarinic M3 receptors, serotonin 5-HT1A receptors, neuropeptide Y receptors, cholecystokinin A receptors, and catecholamines, as well as to ghrelin, leptin, and glucose. Orexinergic neurons themselves regulate release of acetylcholine, serotonin and noradrenaline, 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.
See also
Leptin
References
External links
Category:Endocrinology
Category:Peptide hormones
Category:Neuropeptides
Category:Orexin antagonists
