Article

The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization

Department of Cell Biology, Institut Cochin, Paris, France.
The EMBO Journal (Impact Factor: 10.75). 08/2006; 25(13):3012-23. DOI: 10.1038/sj.emboj.7601193
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ABSTRACT One-third of the approximately 400 nonodorant G protein-coupled receptors (GPCRs) are still orphans. Although a considerable number of these receptors are likely to transduce cellular signals in response to ligands that remain to be identified, they may also have ligand-independent functions. Several members of the GPCR family have been shown to modulate the function of other receptors through heterodimerization. We show that GPR50, an orphan GPCR, heterodimerizes constitutively and specifically with MT(1) and MT(2) melatonin receptors, using biochemical and biophysical approaches in intact cells. Whereas the association between GPR50 and MT(2) did not modify MT(2) function, GPR50 abolished high-affinity agonist binding and G protein coupling to the MT(1) protomer engaged in the heterodimer. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT(1) without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT(1). Pairing orphan GPCRs to potential heterodimerization partners might be of clinical importance and may become a general strategy to better understand the function of orphan GPCRs.

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Available from: Angélique Levoye, Aug 11, 2015
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    • "It is also possible that GPR50's association with depression occurs via its ability to modulate melatonin signaling, as melatonin reportedly plays a role in depression (Singh and Jadhav 2014). While GPR50 does not bind melatonin itself, it has been shown to inhibit binding of melatonin to the melatonin receptor 1 (Levoye et al. 2006), and thus influences signaling. Strengths of our study are that it was populationbased and involved more than 1000 elderly who were followed for over 12 years. "
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    • "Receptor heteromerization can significantly modify functional characteristics of the individual protomers, resulting in new functional entities possessing new biochemical characteristics (Agnati et al., 2003; Prinster et al., 2005; Woods et al., 2005). They include gain in function and changes in pharmacological properties, such as changes in ligand-binding cooperativity, signaling and trafficking/subcellular localization (Agnati et al., 2003; Levoye et al., 2006; Milligan, 2009; Prinster et al., 2005; Springael et al., 2007). Examples of heteromerization involving GPCR are shown in Table 1. "
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    Neuroscience 07/2014; 277. DOI:10.1016/j.neuroscience.2014.06.049 · 3.33 Impact Factor
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    • "It was originally cloned from human pituitary gland and termed melatonin-related receptor (MRR) for its homology with the melatonin receptors (Reppert et al., 1996; Dufourny et al., 2008, 2012). GPR50 does not bind to melatonin, and although it may dimerize with melatonin receptors (possibly influencing melatonin action) to date it remains an orphan receptor (Levoye et al., 2006). Expression of GPR50 is high in the hypothalamus, where it localized in the medial POA, the LH neurons of the dorsomedial nucleus, and in tanycytes (Reppert et al., 1996; Drew et al., 1998, 2001; Hamouda et al., 2007; Sidibe et al., 2010; Batailler et al., 2011; Bechtold et al., 2012). "
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