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Review
. 2022 Apr 13:16:812359.
doi: 10.3389/fncel.2022.812359. eCollection 2022.

Orexin Signaling: A Complex, Multifaceted Process

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
Review

Orexin Signaling: A Complex, Multifaceted Process

Natasha C Dale et al. Front Cell Neurosci. .

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.

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Conflict of interest statement

KP is Chief Scientific Advisor to Dimerix, of which he has a shareholding. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The orexin system. The orexin system consists of two endogenous peptide agonists, OX-A and OX-B, cleaved from the common precursor peptide prepro-orexin. Both agonists have affinity for the two orexin receptors, OX1R and OX2R, although it has been suggested that OX-B has some OX2R selectivity, whereas OX-A is not selective. Following agonist binding, an active conformation of the receptor is stabilized and effector proteins are recruited to induce a cellular response.
FIGURE 2
FIGURE 2
ERK1/2 phosphorylation data for OX1R (OxR1) and OX2R (OxR2) stably transfected in HEK293 cells. (A) Stably transfected HEK293 cells were treated with OX-A (OxA) and measured over a 4-h period. Data were normalized to time-matched vehicle treatments and are expressed as a percentage of the maximal response induced at 2 min post-agonist treatment. Data are expressed as mean ± SE of four independent experiments. *p < 0.05 between OX1R and OX2R from 10 to 120 min post-agonist stimulation. (B) Concentration-response data were collected at 2- and 90-min post OX-A treatment of OX2R-expressing cells. Data are expressed as a percentage of the maximal response induced at the time point (mean ± S.E. of four independent experiments). Reproduced from Dalrymple et al. (2011) under a Creative Commons Attribution 4.0 International License. Full terms provided at https://creativecommons.org/licenses/by/4.0/.
See this image and copyright information in PMC

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