Orexin-A

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Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.

Contents

Structure

Orexin-A is a peptide composed of 33 amino acids including an N-terminal pyroglutamyl residue and two intramolecular disulfide bridges between cysteine residues in 6 and 12 and 7 and 14 positions.[ citation needed ]

The amino acid sequence is: Pyroglu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu. [1] [2]

Mechanism

Orexins are highly excitatory neuropeptides that were first discovered in the brains of rats. It is a peptide that is produced by a very small population of cells in the lateral and posterior hypothalamus. Orexins strongly excite various brain nuclei (neurons) to affect an organism's wakefulness by affecting their dopamine, norepinephrine, histamine and acetylcholine systems. [3]

These systems work together to stabilize the organism's sleep cycles. Once made, the orexin peptides can bind to the orexin receptor; which is a G protein-coupled receptor. This receptor senses molecules outside the cell and activates inside signal transduction pathways to elicit cellular responses.

Research shows that an absence of orexin-A appears to cause narcolepsy. Deficit amounts of orexin-A will make people sleepy and research suggests that by adding it back into the brain, narcoleptic effects will be reduced. The research determined how glucose inhibited a particular class of glucose-sensing neurons, which produce orexins. However, it is unknown how glucose suppresses the electrical activity of orexin cells. [4]

A study from the University of Manchester discovered how glucose-inhibited neurons affected the regulation of sleep cycles. Tests show a class of potassium ion channels, pore-like proteins in the cell membrane, affect the cellular responses by controlling the flow of potassium into the cell. The exact mechanism of the potassium ion channels is unknown, but the experiments show that the presence of glucose inhibited the orexin neurons by acting on this class of potassium ion channels known as "tandem pore" channels. [5]

Ongoing research

The subjects of one particular study, rhesus monkeys, were deprived of sleep in durations of 30 to 36 hours, and were immediately assessed in short term memory tasks. The rhesus monkeys were split into a test group and into a control group. The test group was administered orexin-A, intravenously or nasally. The control group was given a placebo. The sleep-deprived monkeys which were given the nasal form of orexin-A performed far better than the ones treated with injections. Orexin-A not only restored the monkeys' cognitive abilities but made their brains appear awake in PET scans. The same was not true for the control group, which did not exhibit any changes. [6]

Related Research Articles

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Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it. It exists in the forms of orexin-A and orexin-B.

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<span class="mw-page-title-main">Lateral hypothalamus</span>

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<span class="mw-page-title-main">Vasotocin</span> Chemical compound

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<span class="mw-page-title-main">Hypocretin (orexin) receptor 1</span> Protein-coding gene in the species Homo sapiens

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Thomas S. Kilduff is an American neuroscientist and the director of SRI International's Center for Neuroscience. He specializes in neurobiology related to sleep and wakefulness, and was involved in the discovery of hypocretin, a neuropeptide system that is highly involved in wakefulness regulation.

CNMamide (CNMa) is a cyclic neuropeptide identified by computational analysis of Drosophila melanogaster protein sequences and named after its C-terminal ending motif. A gene encoding CNMa was found in most arthropods and comparison among the precursor sequences of several representative species revealed high conservation, particularly in the region of the predicted mature peptide. Two conserved cysteine residues enveloping four amino acids form a disulfide bond and were shown to be important for binding of the peptide to its receptor. Expression of CNMa was confirmed in the larval and adult brain of D. melanogaster but the function of the peptide has not been elucidated yet.

References

  1. ↑ "Amino acid sequence in Orexin A EIA Kit (Human, Rat, Mouse)". Biokitsupply. Retrieved 2008-01-25.
  2. ↑ Johns, A.; Porter, R.A. (1999-11-18). "Amino acid sequence mentioned in "Phenylurea and phenylthio urea derivatives" patent". Google Patents. Retrieved 2008-01-25.
  3. ↑ Claudio L.A. Bassetti; et al. (2019). "Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment". Nature Reviews Neurology. 15 (9): 519–539. doi:10.1038/s41582-019-0226-9. PMID   31324898. S2CID   198132754 . Retrieved 2021-07-03.
  4. ↑ Raffaella Spinazzi; Paola G. Andreis; Gian Paolo Rossi; Gastone G. Nussdorfer (2006). "Orexins in the Regulation of Hypothalamic-Pituitary-Adrenal Axis". Pharmacological Reviews. 58 (1): 46–57. doi:10.1124/pr.58.1.4. PMID   16507882. S2CID   17941978 . Retrieved 2008-01-25.
  5. ↑ Denis Burdakov; et al. (31 May 2006). "New mechanism explains glucose effect on wakefulness". Neuron. Retrieved 2008-01-25.
  6. ↑ Deadwyler, S. A.; et al. (December 26, 2007). "Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates". The Journal of Neuroscience. 27 (52): 14239–14247. doi: 10.1523/JNEUROSCI.3878-07.2007 . PMC   6673447 . PMID   18160631.