Orexins and orexin receptors: from molecules to integrative physiology

Results Probl Cell Differ (46) O. Civelli, Q.-Y. Zhou: Orphan G Protein-Coupled Receptors and Novel Neuropeptides DOI 10.1007/400_2007_047/Published online: 19 January 2008  Springer-Verlag Berlin Heidelberg 2008 Orexins and Orexin Receptors: From Molecules to Integrative Physiology Taizo Matsuki1,2,3 · Takeshi Sakurai1,2,3 (✉) 1 Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, 305-8575 Ibaraki, Japan stakeshi@md.tsukuba.ac.jp 2 Yanagisawa Orphan Receptor Project, ERATO, Japan Science and Technology Agency, 135-0064 Tokyo, Japan 3 Present address: Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Science, Kanazawa University, 920 8640 Kanazawa, Japan Abstract Recent studies have implicated the orexin system as a critical regulator of sleep/wake states, feeding behavior, and reward processes. Orexin deficiency results in narcolepsy-cataplexy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. Orexin agonists and antagonists are thought to be promising avenues toward the treatment of sleep disorders, eating disorders, and drug addiction. In this chapter, we discuss the current understanding of the physiological roles of orexins in regulation of arousal, sleep/wake states, energy homeostasis, and reward systems. 1 Introduction Identification of a transmitter that naturally activates an orphan GPCR is crucial for understanding the physiological roles of a particular ligand-receptor system. Identification of ligands has the potential to define unknown functions and therapeutic targets in novel fields. One of the most compelling cases is the orexin system, in which classical and modern molecular pharmacological approaches have crossed paths, producing spectacular results. Starting from the discovery of molecules (orexins and orexin receptors), identification of the distribution of ligands and receptors predicted the role of this neuropeptide system. Investigations of gene-modified animals led to the finding of previously unknown functions of the orexins (sleep/arousal regulation), as well as the understanding of the pathophysiology of narcolepsy-cataplexy in humans. Anatomical, physiological, and pharmacological approaches to investigating the orexin system resulted in the appreciated knowledge of brain functions and regional networks. Referring to the orexin system is indispensable for research in the field of sleep, feeding, and reward control. Moreover, the possibility of clinical treatment for sleep disorders using antagonists or agonists of orexin receptors has been examined. 28 T. Matsuki · T. Sakurai Since there are many comprehensive reviews on the orexin system (for a recent review, see Sakurai 2007), in this chapter, we will discuss an overview of its physiological significance, in relation to the possibility of clinical utility of orexin antagonists and agonists in the treatment of eating disorders, sleep disorders, and drug addiction. 2 Orexin and Orexin Receptors 2.1 Identification of Orexin (Hypocretin) by Deorphaning of Two GPCRs Both orexin A and B were identified by the orphan GPCR strategy using stably expressing HFGAN72 orexin-1 receptor (OX1 R)-transfected HEK293 cells from rat brain extracts by detecting intracellular Ca2+ mobilization (Sakurai et al. 1998). Orexins constitute a novel peptide family with no significant homology with any previously described peptides. Orexin A is a 33-amino-acid peptide of 3562 Da. It has an N-terminal pyroglutamyl residue and C-terminal amida- Fig. 1 Overview of orexin system. Orexin A and orexin B are derived from a common precursor peptide, prepro-orexin. The actions of orexins are mediated via two G protein-coupled receptors named orexin-1 (OX1 R) and orexin-2 (OX2 R) receptors. OX1 R is selective for orexin A, whereas OX2 R is a nonselective receptor for both orexin A and orexin B. OX1 R is coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas OX2 R couples to Gi/o and/or Gq .