Orexin Signaling: A Complex, Multifaceted Process

Natasha C Dale; Daniel Hoyer; Laura H Jacobson; Kevin D G Pfleger; Elizabeth K M Johnstone

doi:10.3389/fncel.2022.812359

Orexin Signaling: A Complex, Multifaceted Process

Front Cell Neurosci. 2022 Apr 13:16:812359. doi: 10.3389/fncel.2022.812359. eCollection 2022.

Authors

Natasha C Dale^{1

2

3}, Daniel Hoyer^{4

5

6}, Laura H Jacobson^{4

5

7}, Kevin D G Pfleger^{1

2

3

8}, Elizabeth K M Johnstone^{1

2

3

9}

Affiliations

¹ Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia.
² Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, VIC, Australia.
³ Australian Research Council Centre for Personalised Therapeutics Technologies, Perth, WA, Australia.
⁴ Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
⁵ Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.
⁶ Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States.
⁷ Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁸ Dimerix Limited, Nedlands, WA, Australia.
⁹ School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia.

Abstract

The orexin system comprises two G protein-coupled receptors, OX₁ and OX₂ receptors (OX₁R and OX₂R, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system's function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.

Keywords: G protein; GPCR (G protein coupled receptor); arrestin; orexin; orexin 1 receptor; orexin 2 receptor; signaling.

Publication types

Review