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. 2016 Nov;1863(11):2719-2738.
doi: 10.1016/j.bbamcr.2016.07.009. Epub 2016 Aug 12.

Heterodimerization of the kappa opioid receptor and neurotensin receptor 1 contributes to a novel β-arrestin-2-biased pathway

Haiqing Liu  1 , Yanjun Tian  2 , Bingyuan Ji  3 , Hai Lu  4 , Qing Xin  5 , Yunlu Jiang  6 , Liangcai Ding  7 , Jingmei Zhang  8 , Jing Chen  9 , Bo Bai  10
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Free article

Heterodimerization of the kappa opioid receptor and neurotensin receptor 1 contributes to a novel β-arrestin-2-biased pathway

Haiqing Liu et al. Biochim Biophys Acta. 2016 Nov.
Free article

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.

Keywords: GPCR; Heterodimerization; Kappa opioid receptor; Neurotensin receptor 1.

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