Orexin-A, also known as hypocretin-1, is a naturally occurring

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like t ...

and orexin

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...

. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.

Structure

Orexin-A is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

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.

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 A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

) to affect an organism's wakefulness by affecting their

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...

and

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

systems. These systems work together to stabilize the organism's sleep cycles. Once made, the orexin peptides can bind to the

orexin receptor The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ). Both orexin receptors exhibit ...

; which is a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

. 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 Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

inhibited a particular class of glucose-sensing neurons, which produce orexins. However, it is unknown how glucose suppresses the electrical activity of orexin cells. A study from the

University of Manchester The University of Manchester is a public university, public research university in Manchester, England. The main campus is south of Manchester city centre, Manchester City Centre on Wilmslow Road, Oxford Road. The university owns and operates majo ...

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.

Ongoing research

The subjects of one particular study,

rhesus monkeys The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally ...

, were deprived of sleep in durations of 30 to 36 hours, and were immediately assessed in short term

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...

tasks. The rhesus monkeys were split into a test group and into a

control group In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one t ...

. The test group was administered orexin-A, intravenously or nasally. The control group was given a

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

. 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.

References

{{Orexin receptor modulators Molecular neuroscience Neuropeptides Orexin receptor agonists