Orexin Peptides

2018-05-04

Brief information of orexin peptide

The past several years have provided important insights into the physiological significance of the central orexin system. The orexin peptides, orexin-A and orexin-B, are produced in a restricted region of the central nervous system, the neurons of the lateral hypothalamic area. From this small neuronal source, on the order of a few thousand neurons, orexin-expressing neurons project over virtually the entire brain and spinal cord. At the terminals of these projections, orexin interacts with two distinct receptors, the orexin 1 receptor (OX1R) and the orexin 2 receptor (OX2R).

The orexin peptide family consists of two known peptides, orexin-A (OX-A, 33 amino acids) and orexin-B (OX-B, 27 amino acids) which are proteolytically cleaved from one gene product, the prepro-orexin (PPORX) peptide. Whereas the pharmacological and physiological effects of each singular orexin peptide may differ and have yet to be fully characterized, it appears that neurons expressing PPORX likely contain both OX-A and OX-B peptides. Orexin peptides localize within secretory vesicles implying that both ORX-A and ORX-B are coreleased at orexinergic synapses. There is general agreement in immunohistochemical staining for PPORX, ORX-A, and OX-B, further implying that both orexin peptides are produced in orexin containing neurons.

Orexin peptides interact with two known G-protein coupled receptor subtypes, the orexin 1 receptor(OX1R) and orexin 2 receptor(OX2R) which each have slightly different affinities for the orexin peptides. The OX1R is approximately one hundred times more selective for OX-A compared to OX-B, whereas the OX2R is relatively nonselective between the two orexin peptides. These two receptor subtypes are, as yet, the only known receptors which respond to application of orexin peptides. Whereas orexin peptides are produced in the restricted location of the hypothalamus, orexin receptors are expressed in many diverse regions of the brain and spinal cord.

Orexins and Sleep/Wake Regulation

The functional role of the central orexin system has been most strongly linked to central systems controlling sleep/wake states and arousal. Orexins are thought to be a wake promoting neuronal group. Orexin neurons are active during periods of wakefulness. The loss of orexin or of orexin neurons in rodents leads to a narcolepsy-like phenotype, and human narcoleptics are orexin deficient. Furthermore, the loss of orexin receptor signaling can also manifest as a narcolepsy-like phenotype in rodents and dogs. Conversely, both central orexin administration by pharmacological means as well as over expression by transgenic alleles causes wakefulness and can reverse the narcolepsy/cataplexy phenotype of mice without orexin neurons. It is clear that the orexin system is physiologically relevant to regulation of sleep, however the anatomical sites of importance for orexin action remain unclear. While the majority of the work presented here is focused on the autonomic role of the orexin system, the anatomical findings must be considered with respect to regulation of sleep/wake states, cataplexy, and overall vigilance as a whole.

Orexins and Feeding, Metabolism, and Autonomic Tone

Early studies on orexin peptides suggested that orexins may regulate feeding behavior. Intracerebroventricular administration of orexins caused feeding and rodents lacking orexin peptides tend to be hypophagic. Fasting leads to increased production of prepro-orexin and orexin receptor mRNAs. However, subsequent studies revealed that the hyperphagic effect of orexins is dependent on the time of day and not as robust as initially reported. Even so, there is anatomic evidence to support a role for orexins in short-term feeding regulation. Neurons in the arcuate hypothalamic nucleus, some of which express neuropeptide Y and control feeding and body weight homeostasis, are excited by orexin administration. Similarly, MCH neurons in the lateral hypothalamus are activated in response to application of orexins.

Studies on identified orexin neurons have shown that several circulating metabolic cues can acutely influence the activity of orexin neurons. Orexin neurons may directly detect and respond to physiologically relevant rises and falls in circulating glucose. Neurons in the lateral hypothalamus are known to response electrically to changes in extracellular glucose concentrations. Isolated orexin neurons are directly inhibited by increasing glucose concentration and excited by falling glucose concentrations. Hypoglycemia induced by insulin causes an increase in preproorexin mRNA and c-fos induction in orexin neurons. Furthermore, glucoprivation by 2-deoxy-d-glucose leads to increased c-fos expression in orexin neurons. It is therefore possible that orexin neurons may directly sense and respond to hypoglycemia in vivo.

Reference:

Marcus, J. N. (2005). Orexin receptors and the central autonomic system.

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