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A novel phosphorylation site on orexin receptor 1 regulating orexinA-induced GRK2-biased signaling
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Cai, Xin, Wang, Huannan, Wang, Maochang, Wang, Dexiu, Zhang, Zhen, Wei, Ruotong, Gao, Xiang, Zhang, Rumin, Wang, Chunmei and Chen, Jing (2020) A novel phosphorylation site on orexin receptor 1 regulating orexinA-induced GRK2-biased signaling. Cellular Signalling, 75 . 109743. doi:10.1016/j.cellsig.2020.109743 ISSN 0898-6568.
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WRAP-A-novel-phosphorylation-site-orexin-receptor-1-regulating-Chen-2020.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (2432Kb) | Preview |
Official URL: http://dx.doi.org/10.1016/j.cellsig.2020.109743
Abstract
Drug discovery efforts targeting G protein–coupled receptors (GPCRs) have succeeded in developing multiple medications for treating various human diseases including cancer, metabolic disorders, and inflammatory disorders. These medications are broadly classified as either agonists or antagonists that respectively promote or inhibit receptor activation by endogenous stimuli. However, there has been a growing appreciation that GPCR biased signaling between G protein- and β-arrestin-dependent signaling in particular is a promising method for improving drug efficacy and therapy. Orexin receptor 1 (OX1R), a member of the GPCRs, is an important drug target in the central nervous system. In this study, we identified a novel regulatory phosphorylation site (Ser-262) on OX1R that abolished its capability to interact with GRK2, but did not affect its interaction with G proteins, GRK5, or β-arrestin1/2 activation, indicating that Ser-262 is a key amino acid for OX1R internalization that contributes to induction of GRK2-dependent biased signaling via orexin A. Our findings could potentially lead to the development of new drug targets for the prevention and treatment of insomnia, narcolepsy, and substance abuse, with fewer side effects than existing therapies.
| Item Type: | Journal Article | |||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Phosphorylation, Orexins -- Receptors, G proteins -- Receptors | |||||||||||||||
| Journal or Publication Title: | Cellular Signalling | |||||||||||||||
| Publisher: | Elsevier | |||||||||||||||
| ISSN: | 0898-6568 | |||||||||||||||
| Official Date: | November 2020 | |||||||||||||||
| Dates: |
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| Volume: | 75 | |||||||||||||||
| Article Number: | 109743 | |||||||||||||||
| DOI: | 10.1016/j.cellsig.2020.109743 | |||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||
| Publication Status: | Published | |||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||
| Date of first compliant deposit: | 2 September 2020 | |||||||||||||||
| Date of first compliant Open Access: | 19 August 2021 | |||||||||||||||
| RIOXX Funder/Project Grant: |
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