AUTHOR=Dale Natasha C. , Hoyer Daniel , Jacobson Laura H. , Pfleger Kevin D. G. , Johnstone Elizabeth K. M. 

TITLE=Orexin Signaling: A Complex, Multifaceted Process

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.812359

DOI=10.3389/fncel.2022.812359

ISSN=1662-5102

ABSTRACT=<p>The orexin system comprises two G protein-coupled receptors, OX<sub>1</sub> and OX<sub>2</sub> receptors (OX<sub>1</sub>R and OX<sub>2</sub>R, 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 <italic>in vivo</italic> in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.</p>