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Heterodimerization of the kappa opioid receptor and neurotensin receptor 1 contributes to a novel β-arrestin-2–biased pathway
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Liu, Haiqing, Tian, Yanjun, Ji, Bingyuan, Lu, Hai, Xin, Qing, Jiang, Yunlu, Ding, Liangcai, Zhang, Jingmei, Chen, Jing and Bai, Bo (2016) Heterodimerization of the kappa opioid receptor and neurotensin receptor 1 contributes to a novel β-arrestin-2–biased pathway. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1863 (11). pp. 2719-2738. doi:10.1016/j.bbamcr.2016.07.009 ISSN 0167-4889.
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Official URL: http://dx.doi.org/10.1016/j.bbamcr.2016.07.009
Abstract
Together with its endogenous ligands (dynorphin), the kappa opioid receptor (KOR) plays an important role in modulating various physiological and pharmacological responses, with a classical G protein–coupled pathway mediating analgesia and non-G protein–dependent pathway, especially the β-arrestin–dependent pathway, eliciting side effects of dysphoria, aversion, drug-seeking in addicts, or even relapse to addiction. Although mounting evidence has verified a functional overlap between dynorphin/KOR and neurotensin/neurotensin receptor 1 (NTSR1) systems, little is known about direct interaction between the two receptors. Here, we showed that KOR and NTSR1 form a heterodimer that functions as a novel pharmacological entity, and this heterodimer, in turn, brings about a switch in KOR-mediated signal transduction, from G protein–dependent to β-arrestin-2–dependent. This was simultaneously verified by analyzing a KOR mutant (196th residue) that lost the ability to dimerize with NTSR1. We also found that dual occupancy of the heterodimer forced the β-arrestin-2–dependent pathway back into Gi protein–dependent signaling, according to KOR activation. These data provide new insights into the interaction between KOR and NTSR1, and the newly discovered role of NTSR1 acting as a switch between G protein– and β-arrestin–dependent pathways of KOR also suggests a new approach for utilizing pathologically elevated dynorphin/KOR system into full play for its analgesic effect with limited side effects.
Item Type: | Journal Article | |||||||||||||||
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Subjects: | Q Science > QP Physiology | |||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Opioids -- Receptors, G proteins, Arrestins, Drug addiction -- Physiological aspects | |||||||||||||||
Journal or Publication Title: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | |||||||||||||||
Publisher: | Elsevier | |||||||||||||||
ISSN: | 0167-4889 | |||||||||||||||
Official Date: | November 2016 | |||||||||||||||
Dates: |
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Volume: | 1863 | |||||||||||||||
Number: | 11 | |||||||||||||||
Page Range: | pp. 2719-2738 | |||||||||||||||
DOI: | 10.1016/j.bbamcr.2016.07.009 | |||||||||||||||
Status: | Peer Reviewed | |||||||||||||||
Publication Status: | Published | |||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
Date of first compliant deposit: | 21 February 2018 | |||||||||||||||
Date of first compliant Open Access: | 21 February 2018 | |||||||||||||||
RIOXX Funder/Project Grant: |
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