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Cell Surface Targeting of ␮-␦ Opioid Receptor Heterodimers by RTP4

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Cell Surface Targeting of ␮-␦ Opioid Receptor Heterodimers by RTP4 Cell surface targeting of ␮-␦ opioid receptor heterodimers by RTP4 Fabien M. De´ caillot, Raphael Rozenfeld, Achla Gupta, and Lakshmi A. Devi* Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029 Edited by Susan G. Amara, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved August 22, 2008 (received for review April 29, 2008) ␮ opioid receptors are G protein–coupled receptors that mediate heterodimers, respectively. These findings, together with the the pain-relieving effects of clinically used analgesics, such as observation that the development of tolerance correlates with morphine. Accumulating evidence shows that ␮-␦ opioid het- the enhanced surface expression (through externalization) of ␦ erodimers have a pharmacologic profile distinct from those of the receptors in dorsal root ganglion neurons expressing ␮ receptors ␮ or ␦ homodimers. Because the heterodimers exhibit distinct (15), support the idea that mechanisms and/or proteins that signaling properties, the protein and mechanism regulating their modulate the level of ␮-␦ complexes serve as critical factors in levels have significant effects on morphine-mediated physiology. the development of tolerance (16). Thus, the factors influencing We report the characterization of RTP4, a Golgi chaperone, as a the homodimer-to-heterodimer ratio become a key issue in regulator of the levels of heterodimers at the cell surface. We show determining the net effect of an opiate. Moreover, they could that the association with RTP4 protects ␮-␦ receptors from ubiq- redirect the coupling of opioid receptors to a distinct signal uitination and degradation. This leads to increases in surface transduction pathway (17, 18). But very little is known about the heterodimer levels, thereby affecting signaling. Thus, the oligo- events leading to dimerization per se; it continues to be perceived meric organization of opioid receptors is controlled by RTP4, and as a phenomenon resulting from random collision of the part- this governs their membrane targeting and functional activity. This ners. Dimerization likely occurs through a defined sequence of work is the first report of the identification of a chaperone involved events, as has been shown for the subunit assembly of multipro- in the regulation of the biogenesis of a family A GPCR heterodimer. teins complexes, such as AMPA receptors or G proteins (19, 20). The identification of such factors as RTP4 controlling dimerization Here, we show that association with ␦ receptors leads to the will provide insight into the regulation of heterodimers in vivo. specific retention of ␮ receptors in the Golgi compartment, This has implications in the modulation of pharmacology of their resulting in the decreased cell surface expression of both recep- endogenous ligands, and in the development of drugs with specific tors. Coexpression of RTP4, a member of the receptor transport therapeutic effects. protein (RTP) family that is known to participate in the export of odorant and taste receptors (21, 22) leads to enhanced cell enkephalin ͉ G protein-coupled receptors ͉ heroin ͉ surface expression as well as decreased ubiquitination of recep- hetero-oligomerization tors. Our results show that RTP4 regulates the proportion of ␮-␦ heterodimers, leading to changes in the extent of signaling by these receptors, and thus represents a critical factor influencing he dimerization of G protein–coupled receptors (GPCRs) is the action of exogenous and endogenous opioid ligands. Ta widely studied phenomenon that can profoundly modify the pharmacology of interacting partners in vitro. Allosteric Results modulation of ligand binding, alteration in G protein activation, Because very little is known about the cell biological mechanisms and coupling to a new signaling pathway are known to result underlying cell surface expression of family A GPCR het- from GPCR association (1, 2). Thus, a greater level of complex- erodimers, we used the ␮-␦ opioid receptor heterodimer as a ity could arise from in vivo receptor–receptor interactions, model system and examined the events and proteins involved in making dimers promising targets for the development of new their efficient cell surface expression. We found that coexpres- drugs with more specific therapeutic effects (3). Early studies sion of myc-tagged ␦ receptors with FLAG-tagged ␮ receptors using heterologous expression explored the functional outcome led to increased retention of both receptors in an intracellular resulting from the association of two identical (homodimers) or, compartment (Fig. 1). We also observed a similar phenomenon in most cases, two distinct receptors (heterodimers). Recent using HA-tagged ␮ coexpressed with FLAG-tagged ␦ receptors studies have focused on a role for receptor association in their (data not shown), indicating that the interaction was not influ- folding and maturation, that is, GPCR oligomer biosynthesis (4). enced by the type of epitope tag. In contrast, coexpression of Similar to the dimerization-dependent expression known for ␮ receptors with ␣ adrenergic receptors or of ␦ receptors 2A PHARMACOLOGY class C receptors (5), class A receptors have also been found to with ␬ receptors did not lead to intracellular retention of any of require dimerization for enhanced expression (6, 7). In addition, these receptors (Fig. 1A). These results suggest that the in- inefficient targeting of GPCR oligomers in vivo has been shown creased intracellular retention of ␮ by coexpression with ␦ to be the cause of pathophysiology in some cases, thus empha- receptors exhibits receptor type selectivity, which could lead to sizing the importance of the proper receptor assemblage for a reduction in the cell surface expression of the heterodimer. We normal delivery to the cell surface (8, 9). The mechanism examined this using a whole cell binding assay (data not shown) underlying this phenomenon has not been well explored. The three subtypes of opioid receptors, ␮, ␦, and ␬, are known to form homodimers and heterodimers (10). ␮ opioid receptors Author contributions: F.M.D. and R.R. designed research; F.M.D., R.R., and A.G. performed mediate most of the pain-relieving effects of morphine, the research; A.G. contributed new reagents/analytic tools; F.M.D., R.R., and L.A.D. analyzed prototypical analgesic used in clinics (11). The observation that data; and F.M.D. and L.A.D. wrote the paper. antagonism of ␦ receptors or lack of ␦ receptors leads to a The authors declare no conflict of interest. reduction in the tolerance that develops on chronic administra- This article is a PNAS Direct Submission. tion of morphine (12) suggests a possible link between tolerance *To whom correspondence should be addressed. E-mail: [email protected]. and opioid receptor dimerization. Furthermore, a large compo- This article contains supporting information online at www.pnas.org/cgi/content/full/ nent of morphine and 6Ј-GNTI analgesic potency has been 0804106105/DCSupplemental. linked to the presence of ␮-␦ (13) and ␦-␬ (14) receptor © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0804106105 PNAS ͉ October 14, 2008 ͉ vol. 105 ͉ no. 41 ͉ 16045–16050 Downloaded by guest on September 24, 2021 A MOR DOR merged MOR α2A KOR DOR Fig. 2. Coexpression of ␮ and ␦ receptors leads to intracellular rentention of both receptors in the Golgi apparatus. Immunofluoresence images of µ κ µ Neuro2A cells cotransfected with ␮ (Left) and ␦ receptors (Middle). Labeling B 120 C 120 with anti-syntaxin 6 antibody (Middle) as well as TGN38 (Lower) shows that 100 100 intracellular ␮-␦ receptors colocalize with the marker for Golgi apparatus and 80 80 not with that of ER compartment (anti-calnexin antibody; Upper). 60 60 40 40 O.D. 490 nm (% of control) 20 20 0 0 members, RTP4 and RTP2, and found that the increasing δ δ α δ Ctl 2A Ctl Ctl expression of RTP4 led to a concomitant increase in the cell surface expression of both ␮ and ␦ receptors (Fig. 3A), whereas Fig. 1. Coexpression of ␮ and ␦ receptors leads to loss of cell surface ␮ expression of RTP2 did not (data not shown). Cell surface receptors in HEK293 cells. (A) Cell surface expression of receptors shows that expression of ␮ receptors alone was not altered by RTP4. coexpression with myc-tagged ␦ receptors induces a large retention of FLAG- Confocal imaging revealed that expression of RTP4 in ␮-␦ cells tagged ␮ receptors in an intracellular compartment. Coexpression of HA- ␣ ␮ ␦ ␬ led to enhanced cell surface localization and decreased Golgi tagged 2AR with receptor or receptor with FLAG-tagged does not lead ␮ ␦ to intracellular retention supporting the specificity of ␮-␦ interactions. (B) localization of - receptors (Fig. 3B). Taken together, these Quantitation of cell surface expression of receptors shows that coexpression results suggest that RTP4 acts intracellularly to prevent accu- with myc-tagged ␦ receptors but not with HA-tagged ␣2A receptors induces a mulation of ␮-␦ receptors, allowing them to be targeted to the large decrease in FLAG-tagged ␮ receptor expression. Coexpression of ␦ cell surface. receptor does not alter the cell surface expression of FLAG-tagged ␬ receptors in HEK293 cells. (C) Quantitation of cell surface expression of ␦ receptors cotransfected with ␮ receptors in Neuro2A cells. Values are expressed as mean Ϯ standard error of the mean (SEM) (n ϭ 3). A 120 B 80 MOR or surface enzyme-linked immunosorbent assay (ELISA) (Fig. 1 40 ␦ O.D. 490 nm (% control) B and C). We find
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