Abstract
Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated—with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency—leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review.
Highlights
The orexin/hypocretin system was identified by two groups. de Lecea with colleagues described two putative peptide transmitters, encoded by a propeptide, the gene for which is located at human chromosome 17q21.2 (de Lecea et al, 1998)
While the intracellular OX1408 may affect the receptor interaction with other intracellular or plasma membrane proteins, and the TM6 OX2308 ligand binding, it is not known whether variants at these amino acids result in distinct functional properties, or if the difference might be found in differential processing etc., as suggested by co-segregation of OX2308 Val with the intronic HCRTR2 polymorphisms
Human orexin receptor sequence variation has been investigated in the context of disease-based targeted approaches, first with narcolepsy and with other diseases
Summary
The orexin/hypocretin system was identified by two groups. de Lecea with colleagues described two putative peptide transmitters, encoded by a propeptide, the gene for which is located at human chromosome 17q21.2 (de Lecea et al, 1998). Gene variants for the orexin peptides and, especially, their G protein-coupled receptors, OX1 and OX2, have been identified (Figures 1, 2), and investigated in many CNS disorders, including sleep and wakefulness (Lin et al, 1999), polydipsia in schizophrenia (Meerabux et al, 2005; Fukunaka et al, 2007), panic disorder (Annerbrink et al, 2011), mood disorders (Rainero et al, 2011a), migraine (Schürks et al, 2007b; Rainero et al, 2011b), and cluster headache (Rainero et al, 2004).
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