REVIEW article
Front. Pharmacol.
Sec. Neuropharmacology
Signal transduction, Dimerization, and Therapeutic Targeting of Orexin and Receptor Systems
Provisionally accepted
- Jining Medical University, Jining, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
ABSTRACT Orexin receptors (OXRs), including OX1R (HCRTR1) and OX2R (HCRTR2), are G protein-coupled receptors (GPCRs) that are activated by endogenous orexin peptides (OXA and OXB) and have potential pleiotropic effects in nervous system, which makes them highly valuable therapeutic targets. Emerging evidence indicates that OXRs exhibit a significant propensity to form homodimers and heterodimers with various GPCRs, generating biased signaling that may offer a platform for precision pharmacology and enable the design of pathway-specific drugs with fewer off-target effects. Current and emerging OXR antagonists demonstrate efficacy in sleep disorders, metabolic dysregulation, and psychiatric conditions. Furthermore, transmembrane (TM) peptides targeting specific dimer interfaces represent a novel therapeutic strategy. This review synthesizes current understanding of orexin receptor systems, focusing on the structural composition, signal transduction pathways, dimerization properties, and antagonist compounds of OXRs. We present a comprehensive overview of the current state of research, investigate the molecular pathological mechanisms associated with neurological disorders, and evaluate potential therapeutic targets for pharmaceutical development.
Keywords: GPCRs, GPCR signaling, Neuropharmacology, Neurology, Depression
Received: 02 Sep 2025; Accepted: 11 Nov 2025.
Copyright: © 2025 Zhang, Wang, Ji, Shao, Hou, Chen and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jing Chen, jing.chen@warwick.ac.uk
Chunmei Wang, wangchunmei410@mail.jnmc.edu.cn
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.