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
Source: PubMed

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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    ABSTRACT: IntroductionDespite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G-protein-coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently.Methods Data were obtained from 1010 elderly men and women from the prospective population-based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12-years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations.ResultsAll three variants showed some evidence of an association with late-life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6-fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12-year incidence of depression. In contrast, rs561077 was associated with a 1.8-fold increased risk of incident depression specifically. No significant associations were observed in men.DiscussionOur results thus provide only weak support for the involvement of GPR50 variants in late-life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression).
    Brain and Behavior 02/2015; 5(3). DOI:10.1002/brb3.313
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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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    ABSTRACT: Complex molecular and cellular mechanisms regulate GPCRs. It is suggested that proteins Intrinsically Disordered regions (IDR) are to play a role in GPCR's intra and extracellular regions plasticity, due to their potential for post-translational modification and interaction with other proteins. These regions are defined as lacking a stable three-dimensional (3D) structure. They are rich in hydrophilic and charged, amino acids and are capable to assume different conformation which allows them to interact with multiple partners. In this study we analyzed 75 GPCR involved in synaptic transmission using computational tools for sequence based prediction of intrinsically disordered regions within a protein. We also evaluated putative ligand binding motifs using receptor sequences. The disorder analysis indicated that neurotransmitter GPCRs have a significant amount of disorder in their N-terminus, third Intracellular loop (3IL) and C-terminus. About 31, 39 and 53% of human GPCR involved in synaptic transmission are disordered in these regions. Thirty-three percent of receptors show at least one predicted PEST motif, this being statistically greater than the estimate for the rest of human GPCRs. About 90% of the receptors had at least one putative site for dimerization in their 3IL or C-terminus. The ELM instance sampled in these domains were 14-3-3, SH3, SH2 and PDZ motifs. In conclusion, the increased flexibility observed in GPCRs, added to the enrichment of linear motifs, PEST and heteromerization sites, may be critical for the nervous system's functional plasticity.
    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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    ABSTRACT: Core body temperature (CBT) and calorie intake are main components of energy homeostasis and two important regulators of health, longevity, and aging. In homeotherms, CBT can be influenced by calorie intake as food deprivation or calorie restriction (CR) lowers CBT whereas feeding has hyperthermic effects. The finding that in mice CBT prolonged lifespan independently of CR, suggested that the mechanisms modulating CBT may represent important regulators of aging. Here we summarize the current knowledge on the signaling molecules and their receptors that participate in the regulation of CBT responses to calorie intake. These include hypothalamic neuropeptides regulating feeding but also energy expenditure via modulation of thermogenesis. We also report studies indicating that nutrient signals can contribute to regulation of CBT by direct action on hypothalamic preoptic warm-sensitive neurons that in turn regulate adaptive thermogenesis and hence CBT. Finally, we show the role played by two orphans G protein-coupled receptor: GPR50 and GPR83, that were recently demonstrated to regulate temperature-dependent energy expenditure.
    Frontiers in Genetics 10/2012; 3:184. DOI:10.3389/fgene.2012.00184
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