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=Volume 16 - 2022

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=The orexin system comprises two G protein-coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). When discussing the system’s G protein coupling capabilities, it is commonly stated that both receptors couple to Gq cascades while OX2R also couples to Gi cascades. However, a complex milieu of signalling behaviour has been reported that expands and complicates this narrative. 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.