PMID- 32827691
OWN - NLM
STAT- MEDLINE
DCOM- 20211018
LR  - 20211018
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 75
DP  - 2020 Nov
TI  - A novel phosphorylation site on orexin receptor 1 regulating orexinA-induced 
      GRK2-biased signaling.
PG  - 109743
LID - S0898-6568(20)30220-5 [pii]
LID - 10.1016/j.cellsig.2020.109743 [doi]
AB  - 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 beta-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 beta-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.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Cai, Xin
AU  - Cai X
AD  - School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 
      261042, PR China.
FAU - Wang, Huannan
AU  - Wang H
AD  - Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, PR 
      China; School of Pharmacy, Jining Medical University, Rizhao, Shandong, 276800, 
      PR China.
FAU - Wang, Maochang
AU  - Wang M
AD  - Shouguang Agricultural Development Group Co., Ltd，Shouguang, Shandong, 262700, PR 
      China.
FAU - Wang, Dexiu
AU  - Wang D
AD  - School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 
      261042, PR China.
FAU - Zhang, Zhen
AU  - Zhang Z
AD  - School of Pharmacy, Jining Medical University, Rizhao, Shandong, 276800, PR 
      China.
FAU - Wei, Ruotong
AU  - Wei R
AD  - School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 
      261042, PR China.
FAU - Gao, Xiang
AU  - Gao X
AD  - School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, 
      261042, PR China.
FAU - Zhang, Rumin
AU  - Zhang R
AD  - Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, PR 
      China.
FAU - Wang, Chunmei
AU  - Wang C
AD  - Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, PR 
      China.
FAU - Chen, Jing
AU  - Chen J
AD  - Neurobiology Institute, Jining Medical University, Jining, Shandong, 272067, PR 
      China; Division of Biomedical Sciences, Warwick Medical School, University of 
      Warwick, Coventry, CV4 7AL, UK. Electronic address: jing.chen@warwick.ac.uk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200819
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (HCRTR1 protein, human)
RN  - 0 (Orexin Receptors)
RN  - EC 2.7.11.15 (GRK2 protein, human)
RN  - EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
SB  - IM
MH  - G-Protein-Coupled Receptor Kinase 2/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Orexin Receptors/*metabolism
MH  - Phosphorylation
OTO - NOTNLM
OT  - Biased signaling
OT  - G protein
OT  - G protein-coupled receptor
OT  - Orexin receptor 1
OT  - Therapeutic potential
OT  - beta-Arrestin
COIS- Declaration of Competing Interest The authors confirm that there are no conflicts 
      of interest.
EDAT- 2020/08/23 06:00
MHDA- 2021/10/21 06:00
CRDT- 2020/08/23 06:00
PHST- 2020/05/20 00:00 [received]
PHST- 2020/08/15 00:00 [revised]
PHST- 2020/08/17 00:00 [accepted]
PHST- 2020/08/23 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2020/08/23 06:00 [entrez]
AID - S0898-6568(20)30220-5 [pii]
AID - 10.1016/j.cellsig.2020.109743 [doi]
PST - ppublish
SO  - Cell Signal. 2020 Nov;75:109743. doi: 10.1016/j.cellsig.2020.109743. Epub 2020 
      Aug 19.