RESUMEN
The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy and unusually rapid transitions to rapid-eye-movement sleep, opens a new field of investigation in the area of sleep control physiology. Hypocretin-1 and -2 (also called orexin-A and -B) are newly discovered neuropeptides processed from a common precursor, preprohypocretin. Hypocretin-containing cells are located exclusively in the lateral hypothalamus, with widespread projections to the entire neuroaxis. Two known receptors, Hcrtr1 and Hcrtr2, have been reported. The functional significance of the hypocretin system is rapidly emerging in both animals and humans. Hypocretin abnormalities cause narcolepsy in dogs, human and mice. The role of the hypocretin system in normal sleep regulation is more uncertain. We believe hypocretin cells drive cholinergic and monoaminergic activity across the sleep cycle. Input from the suprachiasmatic nucleus to hypocretin-containing neurons may explain the occurrence of clock-dependent alertness. Other functions are suggested by pharmacological and neurochemical experiments. These include regulation of food intake, neuroendocrine function, autonomic nervous system activity and energy balance.
Asunto(s)
Proteínas Portadoras/fisiología , Péptidos y Proteínas de Señalización Intracelular , Narcolepsia/fisiopatología , Neuropéptidos/fisiología , Sueño/fisiología , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/genética , Ingestión de Alimentos/fisiología , Humanos , Hipotálamo/anatomía & histología , Hipotálamo/fisiología , Modelos Biológicos , Datos de Secuencia Molecular , Narcolepsia/genética , Neuropéptidos/genética , Orexinas , Homología de Secuencia de AminoácidoRESUMEN
We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.