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: 10.43). 08/2006; 25(13):3012-23. DOI: 10.1038/sj.emboj.7601193
Source: PubMed


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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    • "(e.g., MT1/MT1; MT1/MT2; MT2/MT2) configurations within the bilayer lipid membrane to initiate second messenger cascades. For instance, whereas endogenous GPR50/MT2 heterodimers are melatonin responsive, MT1/GPR50 heterodimers are relatively silent to periodic depolarization pulses from pinealocytes (Levoye et al., 2006). The spatiotemporal diversity of these interactions highlights the wide range of GPR50-mediated responses to extracellular signaling events, which in turn converge on processes regulating gene transcription and the synthesis of proteins by local ribosomes. "
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    ABSTRACT: Silent information regulator-1 (SIRT1) deacetylase, a sensor of intermittent energy restriction, is inextricably intertwined with circadian regulation of central and peripheral clock genes. The purpose of this study was to identify SIRT1-specific target genes that are expressed in a circadian rhythm pattern and driven, in part, by specific components of foodstuffs. Using human cells and rats fed with a resveratrol diet we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding the G protein-coupled receptor (GPR), GPR50 in the brain. GPR50 is the mammalian orthologue of the melatonin1c membrane-bound receptor which has been identified as a genetic risk factor for bipolar disorder and major depression in women. In general, our findings support and expand the notion that circadian clock signaling components and dietary interventions are adaptively linked, and suggest that the brain may be particularly sensitive to metabolic events in response to light-dark cycles.
    Frontiers in Molecular Neuroscience 10/2015; 8. DOI:10.3389/fnmol.2015.00061 · 4.08 Impact Factor
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    • "3.4. GPR50 promotes neuronal differentiation through its intracellular domain GPR50 has the longest carboxyl tail among known GPCR [24] [25] and contains at least one putative proteolytic cleavage site [25]. The intracellular domain of GPR50 translocates into the nucleus after binding to TIP60, a transcriptional co-activator with histone acetyltransferase [26]. "
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    ABSTRACT: G protein-coupled receptor 50 (GPR50), a risk factor for major depressive disorder and bipolar affective disorder, is expressed in both the developmental and adult brain. However, the function of GPR50 in the brain remains unknown. We here show GPR50 is expressed by neural progenitor cells (NPCs) in the ventricular zone of embryonic brain. Knockdown of GPR50 with a small interference RNA (siRNA) decreased self-renewal and neuronal differentiation, but not glial differentiation of NPCs. Moreover, overexpression of either full-length GPR50 or the intracellular domain of GPR50, rather than the truncated GPR50 in which the intracellular domain is deleted in, increased neuronal differentiation, indicating that GPR50 promotes neuronal differentiation of NPCs in an intracellular domain-dependent manner. We further described that the transcriptional activity of the intracellular domain of notch on Hes1 gene was repressed by overexpression of GPR50. In addition, decreased levels of transcription factor 7-like 2 (TCF7L2) mRNA was observed in GPR50 siRNA-transfected NPCs, suggesting that knockdown of GPR50 impairs wnt/β-catenin signaling. Moreover, the mRNA levels of neurogenin (Ngn) 1, Ngn2 and cyclin D1, the target genes of notch and wnt/β-catenin signalings, in NPCs were reduced by knockdown of GPR50. Therefore, GPR50 promotes self-renewal and neuronal differentiation of NPCs possibly through regulation of notch and wnt/β-catenin signalings. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 458(4). DOI:10.1016/j.bbrc.2015.02.040 · 2.30 Impact Factor
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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 · 2.24 Impact Factor
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