title: Heterodimerization of the kappa opioid receptor and neurotensin receptor 1 contributes to a novel β-arrestin-2-biased pathway.
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 Giprotein-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.
authors: School of Life Science, Shandong Agricultural University, Taian, Shandong 271018, PR China; Department of Physiology, Taishan Medical College, Taian, Shandong 271000, PR China. Electronic address: liu.haiqing@163.com.
authors: Haiqing
authors: H
authors: Liu
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: tyjj-200@163.com.
authors: Yanjun
authors: Y
authors: Tian
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: jby2006@126.com.
authors: Bingyuan
authors: B
authors: Ji
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: luhai777@126.com.
authors: Hai
authors: H
authors: Lu
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: xinqing6288@163.com.
authors: Qing
authors: Q
authors: Xin
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: fcwrjyl@163.com.
authors: Yunlu
authors: Y
authors: Jiang
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: dliangcai@163.com.
authors: Liangcai
authors: L
authors: Ding
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: 651391333@qq.com.
authors: Jingmei
authors: J
authors: Zhang
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China; Division of Translational and Systems, Warwick Medical School, University of Warwick, Coventry, UK. Electronic address: Jing.Chen@warwick.ac.uk.
authors: Jing
authors: J
authors: Chen
authors: Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China. Electronic address: bbai@mail.jnmc.edu.cn.
authors: Bo
authors: B
authors: Bai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001479:Basal Ganglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D061251:Primary Cell Culture; D011485:Protein Binding; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000605254:ARRB2 protein, human; C000605257:Arrb2 protein, rat; C515653:OPRK1 protein, human; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; D017473:Receptors, Opioid, kappa; D000071560:beta-Arrestin 2; C114036:neurotensin type 1 receptor; C026843:dynorphin (1-13); D004399:Dynorphins; D000242:Cyclic AMP
keywords: GPCR; Heterodimerization; Kappa opioid receptor; Neurotensin receptor 1