International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers

Pin, Jean‐Philippe; Neubig, Richard R.; Bouvier, Michel; Devi, Lakshmi A.; Filizola, Marta; Javitch, Jonathan A.; Lohse, Martin J.; Milligan, Graeme; Palczewski, Krzysztof; Parmentier, Marc; Spedding, Michael

doi:10.1124/pr.59.1.5

Cited by 256 publications

(240 citation statements)

References 87 publications

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“…The in vivo contribution of both receptors, as evidenced by reduced potency of SNC80 in both δ-and μ-knockout animals, is also one of three specific criteria for the establishment of the heteromeric complex established by IUPHAR guidelines. 23 Additionally, our in vitro efficacy data demonstrating selective activation of μ−δ heteromers by SNC80 is further supported by trafficking and binding studies. 17,24 That these trafficking studies revealed SNC80-induced cointernalization of μ-and δ-opioid receptors is consistent with activation of a μ−δ heteromer as the signaling unit.…”

supporting

confidence: 52%

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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supporting

confidence: 52%

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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“…Nonetheless, the mechanism of the interaction mediating receptor heteromerization does not appear to be necessary for the classification of a receptor heteromer as recommended by the International Union of Basic and Clinical Pharmacology (Pin et al, 2007), whereby receptor heteromers can be accepted by the scientific community provided their existence in native tissue has been firmly demonstrated. In line with this, at least two of the following criteria should be met: (1) There is evidence for physical association in native tissues or primary cells, preferably through the use of energy transfer technologies or antibodies selective for specific receptor oligomers (Wager-Miller et al, 2002), (2) A specific functional property for the receptor heteromer is known so receptors in native tissue can be identified, and (3) the existence of the heteromer was confirmed in vivo through the use of knockout animals or RNAi technology.…”

Section: The Receptor Interface: Receptor Homomers Versus Receptor Hementioning

confidence: 99%

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

135

106

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The pharmacological modification of dopamine transmission has long been employed as a therapeutic tool in the treatment of many mental health disorders. However, as many of the pharmacotherapies today are not without significant side effects, or they alleviate only a particular subset of symptoms, the identification of novel therapeutic targets is imperative. In light of these challenges, the recognition that dopamine receptors can form heteromers has significantly expanded the range of physiologically relevant signaling complexes as well as potential drug targets. Furthermore, as the physiology and disease relevance of these receptor heteromers is further understood, their ability to exhibit pharmacological and functional properties distinct from their constituent receptors, or modulate the function of endogenous homomeric receptor complexes, may allow for the development of alternate therapeutic strategies and provide new avenues for drug design. In this review, we describe the emerging neurobiology of the known dopamine receptor heteromers, their physiological relevance in brain, and discuss the potential role of these receptor complexes in neuropsychiatric disease. We highlight their value as targets for future drug development and discuss innovative research strategies designed to selectively target these dopamine receptor heteromers in the search for novel and clinically efficacious pharmacotherapies.

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confidence: 99%

“…Although GPCRs were initially thought to be monomeric, evidence accumulated over the past two decades suggests that they can form dimers or oligomers in intact cells (6)(7)(8)(9)(10). In a few cases, such as the γ-aminobutyric acid type B (GABA B ) receptor and other family-C GPCRs, di-/oligomerization is essential for receptor function (10)(11)(12).…”

mentioning

confidence: 99%

“…In a few cases, such as the γ-aminobutyric acid type B (GABA B ) receptor and other family-C GPCRs, di-/oligomerization is essential for receptor function (10)(11)(12). It is now well established that functional GABA B receptors consist of a GABA B1 subunit (which binds GABA but cannot activate G proteins) and a GABA B2 subunit (which is binding deficient but can signal to G proteins) (10)(11)(12). Interestingly, heterodimerization of GABA B1 with GABA B2 masks an endoplasmic reticulum retention signal on the C-terminal tail of GABA B1 , and this is required for GABA B1 to reach the cell surface (10)(11)(12).…”

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confidence: 99%

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Single-molecule analysis of fluorescently labeled G-protein–coupled receptors reveals complexes with distinct dynamics and organization

Calebiro

Rieken

Wagner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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G-protein-coupled receptors (GPCRs) constitute the largest family of receptors and major pharmacological targets. Whereas many GPCRs have been shown to form di-/oligomers, the size and stability of such complexes under physiological conditions are largely unknown. Here, we used direct receptor labeling with SNAP-tags and total internal reflection fluorescence microscopy to dynamically monitor single receptors on intact cells and thus compare the spatial arrangement, mobility, and supramolecular organization of three prototypical GPCRs: the β 1 -adrenergic receptor (β 1 AR), the β 2 -adrenergic receptor (β 2 AR), and the γ-aminobutyric acid (GABA B ) receptor. These GPCRs showed very different degrees of di-/oligomerization, lowest for β 1 ARs (monomers/dimers) and highest for GABA B receptors (prevalently dimers/tetramers of heterodimers). The size of receptor complexes increased with receptor density as a result of transient receptor-receptor interactions. Whereas β 1 -/ β 2 ARs were apparently freely diffusing on the cell surface, GABA B receptors were prevalently organized into ordered arrays, via interaction with the actin cytoskeleton. Agonist stimulation did not alter receptor di-/oligomerization, but increased the mobility of GABA B receptor complexes. These data provide a spatiotemporal characterization of β 1 -/β 2 ARs and GABA B receptors at single-molecule resolution. The results suggest that GPCRs are present on the cell surface in a dynamic equilibrium, with constant formation and dissociation of new receptor complexes that can be targeted, in a ligand-regulated manner, to different cell-surface microdomains.live cell imaging | protein-protein interactions

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International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers

Cited by 256 publications

References 87 publications

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

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

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Single-molecule analysis of fluorescently labeled G-protein–coupled receptors reveals complexes with distinct dynamics and organization

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