Orexin-A

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.

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.

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 neuropeptide 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. 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 G protein linked 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 tiny proteins called orexins. However, it is unknown how glucose suppresses the electrical activity of orexin cells.[3]

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.[4]

Effects of supplementation

To date, orexin-A has shown no negative side effects. Positive side effects include an improvement in cognitive ability and functionality in a sleep deprived state. Taking orexin-A also increases arousal, alertness, attention, and muscle tone. Orexin-A has no effect on subjects who are well rested. The most important side effect orexin-A is thought to have is counteracting the effects of narcolepsy.[5][6][7][8]

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 monkey’s 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. The findings of these studies strongly favor an effective way to alleviate cognitive limitations due to sleep loss.[9]

References

  1. ↑ "Amino acid sequence in Orexin A EIA Kit (Human, Rat, Mouse)". Biokitsupply. Retrieved 2008-01-25.
  2. ↑ Johns, A. and Porter, R.A. (1999-11-18). "Amino acid sequence mentioned in "Phenylurea and phenylthio urea derivatives" patent". Google Patents. Retrieved 2008-01-25.
  3. ↑ Raffaella Spinazzi, Paola G. Andreis, Gian Paolo Rossi and Gastone G. Nussdorfer (2006). "Orexins in the Regulation of Hypothalamic-Pituitary-Adrenal Axis". Pharmalogical Reviews. Retrieved 2008-01-25.
  4. ↑ Denis Burdakov; et al. (31 May 2006). "New mechanism explains glucose effect on wakefulness". Neuron. Retrieved 2008-01-25.
  5. ↑ 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.
  6. ↑ Stanford Center for Narcolepsy FAQ (retrieved 27-Mar-2012)
  7. ↑ http://healthysleep.med.harvard.edu/narcolepsy/credits (2013-07-22). "Developing new treatments for Narcolepsy". Division of Sleep Medicine at Harvard Medical School. Retrieved 2016-10-19.
  8. ↑ Alexis Madrigal (2007-12-28). "Snorting a Brain Chemical Could Replace Sleep". Wired. Retrieved 2008-01-25.
  9. ↑ 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. PMID 18160631. Retrieved 2008-01-25.
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