Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation

He, Shao Qiu; Zhang, Zhenning; Guan, Ji‐Song; Liu, Hong Rui; Zhao, Bo; Wang, Hai Bo; Li, Qian; Hong, Yang; Luo, Jie; Li, Zi Yan; Wang, Qiong; Lü, Ying; Liu, Bao; Zhang, Xu

doi:10.1016/j.neuron.2010.12.001

Cited by 205 publications

(244 citation statements)

References 55 publications

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“…Of particular interest is the regulation and trafficking of dimerized GPCRs after activation of one of the receptor protomers. A recent study showed that depending on the activating ligand, internalized DOR and -opioid receptor (MOR) heterodimers are either recycled or sorted to lysosomes for degradation (He et al, 2011). DOR is known to internalize and traffic to lysosomes after ligand stimulation (Tsao et al, 2001), whereas agonist-activated MOR is internalized and efficiently recycled, which is important for cellular resensitization (Qiu et al, 2003).…”

Section: Gpcrs and Transubiquitinationmentioning

confidence: 99%

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Dores

Trejo

2012

Mol Pharmacol

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G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development.

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Section: Gpcrs and Transubiquitinationmentioning

confidence: 99%

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Dores

Trejo

2012

Mol Pharmacol

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“…16,17 The rightward shift in the SNC80 dose−response curve in both μ-KO and δ-KO mice demonstrates that both μ-and δ-opioid receptor protomers in the heteromeric complex contribute to the antinociceptive activity of SNC80 in wild-type mice. This result is consistent with prior studies showing that SNC80-induced antinociception possesses both δ-and μ-opioid receptor-mediated 21,22 components.…”

mentioning

confidence: 97%

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

Metcalf

Yekkirala

Powers

et al. 2012

ACS Chem. Neurosci.

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Coexpressed and colocalized μ-and δ-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-proteinmediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing μ−δ heteromers than in all other cell lines. Intrathecal SNC80 administration in μ-and δ-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates μ−δ heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates δ-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric μ−δ receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo. KEYWORDS: μ opioid receptor, δ opioid receptor, μ−δ heteromer, SNC80, knockout, antinociception C ompound SNC80 (Figure 1) has been employed as the prototypic nonpeptide, selective δ-opioid receptor agonist for nearly 20 years. The experimental techniques employed to define the δ-selectivity of SNC80 included radioligand binding, smooth muscle assays, and in vivo antagonism studies employing selective δ-antagonists. 1−4 SNC80 has found broad recognition and adoption as a selective δ-agonist standard, occupying the previously vacant nonpeptide selective δ-agonist niche in the opioid pharmacological toolbox. 3 However, in view of the discovery of opioid receptor heteromers as targets for ligands over the past decade, it is possible that opioid receptor heteromers may be activated by SNC80. In this regard, three heteromers, μ−δ, 5 μ−κ, 6 and κ−δ, 7 have been established in heterologous cell lines, 8 and selective ligands that target these heteromers have been identified for each of the above heteromers. 9−11 Moreover, heteromeric μ−δ receptors have been detected using selective antibodies in both cultured cells and DRG neurons. 12 Thus, δ-receptors organized as heteromers could be relevant in the action of SNC80.In this regard, SNC80-treated μ-opioid receptor knockout (μ-KO) mice have been found to be without effect in a visceral antiwrithing test. 13 Also, SNC80 produced an antihyperalgesic effect in WT mice but lacked this effect in μ-KO mice, 14 an effect similar to a separate study in δ-KO mice. 15 Additionally, in vitro studies on the effects of SNC80 on opioid receptors suggested the involvement of μ-opioid receptors on the activity of SNC80. These included the finding that colocalized μ-and δ-opioid receptors in large and small dorsal root ganglion (DRG) neurons 16 are cointernalized into the same subcellular compartment for lysosomal degradation upon treatment with

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“…Zhang proposed a model of the correlation between the ratio of surface μ and δ opioid receptors and the development of morphine tolerance (Zhang et al, 2006). To explore the relationship of opioid receptor interaction with morphine tolerance, they found that activation of δ opioid receptor caused co-internalization and co-degradation of μ and δ opioid receptors, and the dissociation of these two receptors reduced morphine tolerance (He et al, 2011). This study was listed as a feature article and one of the articles in "pain and itch" topic of Neuron in 2011.…”

Section: Identification Of Opioid Receptor Interaction and Its Role Rmentioning

confidence: 99%

Profile of Dr. Xu Zhang

2017

Sci. China Life Sci.

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research is mainly focused on the molecular and cellular mechanisms of neural diseases, such as chronic pain and X-linked intellectual disability. He has found the changes in gene expression patterns of somatosensory ganglia and the spinal cord after nerve injury and inflammation, and several important mechanisms for regulating the functions of neuropeptides, opioid receptors, Na + /K + pump and voltage-gated sodium channel in the nociceptive sensory neurons. He has also explored the genes related to mental retardation and their underlying mechanisms.

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Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation

Cited by 205 publications

References 55 publications

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors

Profile of Dr. Xu Zhang

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