ArticleThe Journal of biological chemistry2011
Temporal profiling of orexin receptor-arrestin-ubiquitin complexes reveals differences between receptor subtypes.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 42 citations in OpenAlex.
- Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS.Annals of neurology · 2023Trial
- Orexins and neuregulins as exemplars of peptide physiology in the brain: experimental challenges and implications for neuropathology.Frontiers in cellular neuroscience · 2026Article
- Mass Spectrometry-Based Quantification of Orexin Species in Human Cerebrospinal Fluid Reveals Differential Dynamics Associated with Sleep.medRxiv : the preprint server for health sciences · 2025Article
- Orexin and Lifestyle Habits: A Meaningful Connection Among Nutrition, Physical Activity, and Sleep Pattern in Health and Diseases.International journal of molecular sciences · 2025Review
- Signal transduction, dimerization, and therapeutic targeting of Orexin and receptor systems.Frontiers in pharmacology · 2025Review
- A molecular network map of orexin-orexin receptor signaling system.Journal of cell communication and signaling · 2023Article
- Orexin Signaling: A Complex, Multifaceted Process.Frontiers in cellular neuroscience · 2022Review
- Orexin receptors in GtoPdb v.2021.3.IUPHAR/BPS guide to pharmacology CITE · 2021Article
- Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins onFrontiers in physiology · 2019Article
- The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases.Frontiers in molecular neuroscience · 2018Review
- Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics.Pharmaceuticals (Basel, Switzerland) · 2017Article
- Fluorescence- and bioluminescence-based approaches to study GPCR ligand binding.British journal of pharmacology · 2016Review
- Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA?CNS drugs · 2014Review
- OX1 and OX2 orexin/hypocretin receptor pharmacogenetics.Frontiers in neuroscience · 2014Review
- Homogeneous time-resolved fluorescence-based assay to monitor extracellular signal-regulated kinase signaling in a high-throughput format.Frontiers in endocrinology · 2014Article
- Biophysical Detection of Diversity and Bias in GPCR Function.Frontiers in endocrinology · 2014Review
- Article
- Molecular determinants of orexin receptor-arrestin-ubiquitin complex formation.British journal of pharmacology · 2014Article
- Toward an understanding of agonist binding to human Orexin-1 and Orexin-2 receptors with G-protein-coupled receptor modeling and site-directed mutagenesis.Biochemistry · 2013Article
- Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Orexin G protein-coupled receptors (OxRs) and their cognate agonists have been implicated in a number of disorders since their recent discovery, ranging from narcolepsy to formation of addictive behavior. Bioluminescence resonance energy transfer assays of agonist-occupied OxRs provided evidence for a strong dose-dependent interaction with both trafficking proteins β-arrestin 1 and 2 that required unusually high agonist concentrations compared with inositol phosphate signaling. This appears to be reflected in functional differences in potency with respect to orexin A (OxA) and OxR2-dependent ERK1/2 phosphorylation after 90 min compared with 2 min, potentially consistent with β-arrestin-mediated versus G protein-mediated signaling, respectively. Furthermore, extended bioluminescence resonance energy transfer kinetic data monitoring OxA-dependent receptor-β-arrestin and β-arrestin-ubiquitin proximity suggested subtype-specific differences in receptor trafficking, with OxR2 activation resulting in more sustained receptor-β-arrestin-ubiquitin complex formation than elicited by OxR1 activation. Enzyme-linked immunosorbent assay (ELISA) data also revealed that OxR1 underwent significantly more rapid recycling compared with OxR2. Finally, we have observed sustained OxA-dependent ERK1/2 phosphorylation in the presence of OxR2 compared with OxR1. Although both OxR subtypes could be classified as class B receptors for β-arrestin usage based on the initial strength of interaction with both β-arrestins, our temporal profiling revealed tangible differences between OxR subtypes. Consequently, OxR1 appears to fit uneasily into the commonly used β-arrestin classification scheme. More importantly, it is hoped that this improved profiling capability, enabling the subtleties of protein complex formation, stability, and duration to be assessed in live cells, will help unlock the therapeutic potential of targeting these receptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.