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Orexin/hypocretin receptor signalling: a functional perspective.

ABSTRACT: Multiple homeostatic systems are regulated by orexin (hypocretin) peptides and their two known GPCRs. Activation of orexin receptors promotes waking and is essential for expression of normal sleep and waking behaviour, with the sleep disorder narcolepsy resulting from the absence of orexin signalling. Orexin receptors also influence systems regulating appetite/metabolism, stress and reward, and are found in several peripheral tissues. Nevertheless, much remains unknown about the signalling pathways and targets engaged by native receptors. In this review, we integrate knowledge about the orexin receptor signalling capabilities obtained from studies in expression systems and various native cell types (as presented in Kukkonen and Leonard, this issue of British Journal of Pharmacology) with knowledge of orexin signalling in different tissues. The tissues reviewed include the CNS, the gastrointestinal tract, the pituitary gland, pancreas, adrenal gland, adipose tissue and the male reproductive system. We also summarize the findings in different native and recombinant cell lines, especially focusing on the different cascades in CHO cells, which is the most investigated cell line. This reveals that while a substantial gap exists between what is known about orexin receptor signalling and effectors in recombinant systems and native systems, mounting evidence suggests that orexin receptor signalling is more diverse than originally thought. Moreover, rather than being restricted to orexin receptor 'overexpressing' cells, this signalling diversity may be utilized by native receptors in a site-specific manner.

SUBMITTER: Leonard CS

PROVIDER: S-EPMC3904253 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Orexin/hypocretin receptor signalling: a functional perspective.

Leonard C S CS Kukkonen J P JP

British journal of pharmacology 20140101 2

Multiple homeostatic systems are regulated by orexin (hypocretin) peptides and their two known GPCRs. Activation of orexin receptors promotes waking and is essential for expression of normal sleep and waking behaviour, with the sleep disorder narcolepsy resulting from the absence of orexin signalling. Orexin receptors also influence systems regulating appetite/metabolism, stress and reward, and are found in several peripheral tissues. Nevertheless, much remains unknown about the signalling pathw ...[more]

PMID: 23848055

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Project description:The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

Dataset Information

Orexin/hypocretin receptor signalling: a functional perspective.

Publications

Orexin/hypocretin receptor signalling: a functional perspective.

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