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GPR50

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Target id: 107

Nomenclature: GPR50

Family: Class A Orphans

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 617 Xq28 GPR50 G protein-coupled receptor 50 10
Mouse 7 591 X 36.98 cM Gpr50 G-protein-coupled receptor 50 10
Rat 3 119 17p12 Gpr50 G protein-coupled receptor 50
Previous and Unofficial Names Click here for help
MTNRL | H9 | Mel1c | melatonin-related receptor
Database Links Click here for help
Specialist databases
GPCRdb mtr1l_human (Hs), mtr1l_mouse (Mm)
Other databases
Alphafold Q13585 (Hs), O88495 (Mm), Q62953 (Rn)
ChEMBL Target CHEMBL3341577 (Hs)
Ensembl Gene ENSG00000102195 (Hs), ENSMUSG00000056380 (Mm), ENSRNOG00000011335 (Rn)
Entrez Gene 9248 (Hs), 14765 (Mm), 117097 (Rn)
Human Protein Atlas ENSG00000102195 (Hs)
KEGG Gene hsa:9248 (Hs), mmu:14765 (Mm), rno:117097 (Rn)
OMIM 309200 (Hs), 300207 (Hs)
Pharos Q13585 (Hs)
RefSeq Nucleotide NM_004224 (Hs), NM_010340 (Mm), NM_001191915 (Rn)
RefSeq Protein NP_004215 (Hs), NP_034470 (Mm), NP_001178844 (Rn)
UniProtKB Q13585 (Hs), O88495 (Mm), Q62953 (Rn)
Wikipedia GPR50 (Hs)
Tissue Distribution Click here for help
Hypothalamus, pituitary
Species:  Human
Technique:  Northern blot
References:  20
Pituitary, epidermal keratinocytes, SBCE2 and WM35 (melanoma cell lines)
Species:  Human
Technique:  RT-PCR
References:  23
Epithelial basal cells, sweat gland cells, hair follicle, fibroblasts of hypertrophic scar tissue but not normal skin
Species:  Human
Technique:  Immunohistochemistry
References:  25
Pituitary, dorsomedial hypothalamus, tanycytes and median eminence
Species:  Human
Technique:  Immunohistochemistry
References:  22
Retina, testis, kidney
Species:  Mouse
Technique:  Northern blot
References:  13
Dorsomedial nucleus of the hypothalamus
Species:  Mouse
Technique:  In situ hybridization, laser-capture microdissection and transcriptional profiling, RT-PCR
References:  15
Ependymal cells
Species:  Mouse
Technique:  GPR50 null mouse in which GPR50 coding sequence has been interrupted by a β-galactosidase (lacZ) coding sequence. This transgenic mouse translates the interrupted GPR50 mRNA sequence to produce a GPR50-lacZ fusion protein, which can be detected by the presence of the chromogenic substrate 5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-gal staining)
References:  19
Ependymal layer of third ventricle and dorsomedial nucleus of the hypothalamus
Species:  Mouse
Technique:  In situ hybridization, β-galactosidase activity
References:  12
Pituitary, dorsomedial hypothalamus, tanycytes and median eminence
Species:  Mouse
Technique:  Immunohistochemistry
References:  22
Hypothalamus, dorsomedial hypothalamus, periventricular nucleus, ependymal cells of the third ventricle, median eminence, lateral preoptic area, laminae terminalis (subfornical organ, vascular organ), lateral septal nucleus (ventral), medial amygdaloid nucleus (anterodorsal)
Species:  Mouse
Technique:  Immunohistochemistry
References:  3
Hypothalamus (periventricular nucleus, ependymal cells of the third ventricle, parenchyma, median eminence, pars tuberalis), dorsomedial hypothalamus, medial preoptic nucleus, dorsal hippocampus (CA1 pyramidal neurons), central amygdaloid nucleus (lateral division)
Species:  Rat
Technique:  Immunohistochemistry, Western blot
References:  3
Pituitary, dorsomedial hypothalamus, tanycytes and median eminence
Species:  Rat
Technique:  Immunohistochemistry
References:  22
Tissue Distribution Comments
In situ hybridisation revealed restricted expression of GPR50 in the ependymal layer, extending from caudal hypothalamic sections through to the beginning of the retrochiasmatic nucleus. Photoperiodic regulation of GPR50 is observed in tanycytes of the ependymal layer [2]. Polyclonal antibodies are now available for detection of human GPR50, which map to different epitopes corresponding to the N-terminus, C-terminus and two additional regions within the intracellular tail. Antibodies are sufficiently sufficient to detect GPR50 in rat pituitary and human hippocampus [11].
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
GPR50 heterodimerizes constitutively and specifically with MT1 and MT2 melatonin receptors
Species:  Human
Tissue:  HEK 293 cells
Response measured:  Association between GPR50 and MT2 did not modify MT2 function. GPR50 abolished high-affinity agonist binding and G protein coupling to the MT1 protomer engaged in the heterodimer. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT1 without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT1
References:  16
Co-expression with TIP60 increased perinuclear localisation of full length GPR50, and resulted in nuclear translocation of the cytoplasmic tail of the receptor
Species:  Human
Tissue:  Identified in a yeast-two-hybrid screen, and confirmed by co-immunoprecipitation and co-localisation in HEK293 cells
Response measured:  GPR50 can enhance TIP60-coactiavtion of glucocorticoid receptor (GR) signalling
References:  17
Interaction between GPR50 and neuronal NOGO-A in mammalian cells causes enrichment of both proteins at the synapse
Species:  Mouse
Tissue:  Mouse (cortical neurons)
Response measured:  Neurite outgrowth
References:  9
Physiological Functions Comments
Physiological function of GPR50 remains unclear, although studies implicate the receptor in energy homeostasis [12].
Physiological Consequences of Altering Gene Expression Click here for help
GPR50 mice maintained on normal chow exhibit lower body weight than age-matched controls. Furthermore, knockout mice are partially resistant to diet induced obesity. Weight gain and body fat content are attenuated despite higher food intake on high energy diets. There is no alteration of circadian period, though overall levels of activity and basal metabolic rate are significantly increased
Species:  Mouse
Tissue:  Brain
Technique:  Gene knockouts
References:  12
GPR50 overexpression increases neurite length and filopodia- and laellipodia-like structures in differentiated Neuroscreen-1 cells
Species:  Human
Tissue:  Neuroscreen-1 cells
Technique:  Gene over-expression
References:  9
Decreased thermogenesis in GPR50 knockout mice is not due to a deficit in adipose tissue, rather attenuated responses to leptin and suppression of thyrotropin-releasing hormone. GPR50 knockout mice are much more likely than wild-type mice to enter fasting-induced torpor, and are much more sensitive to the hypothermia-inducing agent 2-deoxyglucose
Species:  Mouse
Tissue:  Hypothalamus
Technique:  Gene knockout
References:  4
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0002089 abnormal postnatal growth/weight/body size PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0005459 decreased percent body fat PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0001399 hyperactivity PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0008963 increased carbon dioxide production PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0003909 increased eating behavior PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0005289 increased oxygen consumption PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0005659 increased resistance to diet-induced obesity PMID: 17957037 
Gpr50tm1Dgen Gpr50tm1Dgen/Gpr50tm1Dgen
involves: C57BL/6		 MGI:1333877  MP:0008489 postnatal slow weight gain PMID: 17957037 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Major affective disorder 2; MAFD2
Synonyms: Bipolar affective disorder
OMIM: 309200
Comments:  A role for GPR50 in mental disorders, such as Alzheimer's and schizophrenia, has been postulated .
References:  8-9
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Deletion Human Δ502-505 polymorphism 18
Clinically-Relevant Mutations and Pathophysiology Comments
There is an association between the 502-505 deletion polymorphism and age of onset of bipolar disorder (p = 0.049), number of episodes (p = 0.044), hypomanic symptoms (p = 0.019), and initial thinking time (p = 0.027), in women; and in family history of depression in men [18]. No significant association was found between GPR50 human missense polymorphism I606V and adolescent idiopathic scoliosis [21]. GPR50(Δ502-505), or a variant in tight linkage disequilibrium with this polymorphism, may be a sex-specific risk factor for susceptibility to bipolar disorder, and other variants in the gene may be sex-specific risk factors in the development of schizophrenia [24]. This finding was not replicated in a second study in a Northern Swedish population [1]. Additionally no association was seen between haplotypes or SNPs of GPR50 and childhood-onset mood disorders [7]. Significant association between Autistic Spectrum Disorder and two in GPR50, Δ502-505 and T532A, has been shown, but this does not stand up to post-hoc testing. A second study found no variants linked to ASD [6], [14]. Carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels, replicated in two sets of 500 and 585 subjects. C-16X2GPR50T carriers were also shown to have significantly lower circulating HDL-cholesterol levels than wild-type subjects [5]. Seasonal Affective Disorder has been associated with a GPR50 SNP (intronic rs2072621) in females [4].
Biologically Significant Variants Click here for help
Type:  Naturally occurring SNP
Species:  Human
Description:  T532A is present in 45% of the global population, but has a MAF of only 29% in the Asian population. There is currently no phenotype associated with this SNP.
SNP accession:  rs561077
Type:  Naturally occurring SNP
Species:  Human
Description:  Intron polymorphism may be associated with schizophrenia in females. This polymorphism has a global MAF of 29% (30% AFR, 23% AMR, 10% ASN, 44% EUR).
SNP accession:  rs2072621
References:  24
Type:  Naturally occurring SNP
Species:  Human
Description:  I606V substitution may show a weak association with major depressive disorder (MDD) in females. This polymorphism has a global MAF of 31% (25% AFR, 30% AMR, 1% ASN, 57% EUR).
Amino acid change:  I606V
SNP accession:  rs13440581
References:  24
General Comments
GPR50 (melatonin-related receptor) is structurally related to the melatonin receptors, MT1 and MT2, but does not bind melatonin, and its endogenous ligand has not been identified. GPR50 heterodimerises constitutively and specifically with MT1 to abolish high-affinity agonist binding and G protein coupling. Although GPR50 also heterodimerizes with MT2, this had no effect on function in intact cells [16].

References

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1. Alaerts M, Venken T, Lenaerts AS, De Zutter S, Norrback KF, Adolfsson R, Del-Favero J. (2006) Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population. Psychiatr Genet, 16 (6): 235-6. [PMID:17106423]

2. Barrett P, Ivanova E, Graham ES, Ross AW, Wilson D, Plé H, Mercer JG, Ebling FJ, Schuhler S, Dupré SM, Loudon A, Morgan PJ. (2006) Photoperiodic regulation of cellular retinol binding protein, CRBP1 [corrected] and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster. J Endocrinol, 191 (3): 687-98. [PMID:17170225]

3. Batailler M, Mullier A, Sidibe A, Delagrange P, Prévot V, Jockers R, Migaud M. (2012) Neuroanatomical distribution of the orphan GPR50 receptor in adult sheep and rodent brains. J Neuroendocrinol, 24 (5): 798-808. [PMID:22512326]

4. Bechtold DA, Sidibe A, Saer BR, Li J, Hand LE, Ivanova EA, Darras VM, Dam J, Jockers R, Luckman SM et al.. (2012) A role for the melatonin-related receptor GPR50 in leptin signaling, adaptive thermogenesis, and torpor. Curr Biol, 22 (1): 70-7. [PMID:22197240]

5. Bhattacharyya S, Luan J, Challis B, Keogh J, Montague C, Brennand J, Morten J, Lowenbeim S, Jenkins S, Farooqi IS, Wareham NJ, O'Rahilly S. (2006) Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels. J Lipid Res, 47 (4): 761-6. [PMID:16436372]

6. Chaste P, Clement N, Mercati O, Guillaume JL, Delorme R, Botros HG, Pagan C, Périvier S, Scheid I, Nygren G, Anckarsäter H, Rastam M, Ståhlberg O, Gillberg C, Serrano E, Lemière N, Launay JM, Mouren-Simeoni MC, Leboyer M, Gillberg C, Jockers R, Bourgeron T. (2010) Identification of pathway-biased and deleterious melatonin receptor mutants in autism spectrum disorders and in the general population. PLoS ONE, 5 (7): e11495. [PMID:20657642]

7. Feng Y, Wigg K, King N, Vetró A, Kiss E, Kapornai K, Mayer L, Gádoros J, Kennedy JL, Kovacs M, Barr CL, International Consortium for Childhood-Onset Mood Disorders. (2007) GPR50 is not associated with childhood-onset mood disorders in a large sample of Hungarian families. Psychiatr Genet, 17 (6): 347-50. [PMID:18075476]

8. Gerwins P, Nordstedt C, Fredholm BB. (1990) Characterization of adenosine A1 receptors in intact DDT1 MF-2 smooth muscle cells. Mol Pharmacol, 38 (5): 660-6. [PMID:2172773]

9. Grünewald E, Kinnell HL, Porteous DJ, Thomson PA. (2009) GPR50 interacts with neuronal NOGO-A and affects neurite outgrowth. Mol Cell Neurosci, 42 (4): 363-71. [PMID:19699797]

10. Gubitz AK, Reppert SM. (1999) Assignment of the melatonin-related receptor to human chromosome X (GPR50) and mouse chromosome X (Gpr50). Genomics, 55 (2): 248-51. [PMID:9933574]

11. Hamouda HO, Chen P, Levoye A, Sözer-Topçular N, Daulat AM, Guillaume JL, Ravid R, Savaskan E, Ferry G, Boutin JA, Delagrange P, Jockers R, Maurice P. (2007) Detection of the human GPR50 orphan seven transmembrane protein by polyclonal antibodies mapping different epitopes. J Pineal Res, 43 (1): 10-5. [PMID:17614830]

12. Ivanova EA, Bechtold DA, Dupré SM, Brennand J, Barrett P, Luckman SM, Loudon AS. (2008) Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse. Am J Physiol Endocrinol Metab, 294 (1): E176-82. [PMID:17957037]

13. Jockers R, Maurice P, Boutin JA, Delagrange P. (2008) Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?. Br J Pharmacol, 154 (6): 1182-95. [PMID:18493248]

14. Jonsson L, Ljunggren E, Bremer A, Pedersen C, Landén M, Thuresson K, Giacobini M, Melke J. (2010) Mutation screening of melatonin-related genes in patients with autism spectrum disorders. BMC Med Genomics, 3: 10. [PMID:20377855]

15. Lee S, Bookout AL, Lee CE, Gautron L, Harper MJ, Elias CF, Lowell BB, Elmquist JK. (2012) Laser-capture microdissection and transcriptional profiling of the dorsomedial nucleus of the hypothalamus. J Comp Neurol, 520 (16): 3617-32. [PMID:22473294]

16. Levoye A, Dam J, Ayoub MA, Guillaume JL, Couturier C, Delagrange P, Jockers R. (2006) The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J, 25 (13): 3012-23. [PMID:16778767]

17. Li J, Hand LE, Meng QJ, Loudon AS, Bechtold DA. (2011) GPR50 interacts with TIP60 to modulate glucocorticoid receptor signalling. PLoS ONE, 6 (8): e23725. [PMID:21858214]

18. Macintyre DJ, McGhee KA, Maclean AW, Afzal M, Briffa K, Henry B, Thomson PA, Muir WJ, Blackwood DH. (2010) Association of GPR50, an X-linked orphan G protein-coupled receptor, and affective disorder in an independent sample of the Scottish population. Neurosci Lett, 475 (3): 169-73. [PMID:20371266]

19. McCormick MB, Coulombe PA, Fuchs E. (1991) Sorting out IF networks: consequences of domain swapping on IF recognition and assembly. J Cell Biol, 113 (5): 1111-24. [PMID:1710225]

20. Reppert SM, Weaver DR, Godson C. (1996) Melatonin receptors step into the light: cloning and classification of subtypes. Trends Pharmacol Sci, 17 (3): 100-2. [PMID:8936344]

21. Shyy W, Wang K, Gurnett CA, Dobbs MB, Miller NH, Wise C, Sheffield VC, Morcuende JA. (2010) Evaluation of GPR50, hMel-1B, and ROR-alpha melatonin-related receptors and the etiology of adolescent idiopathic scoliosis. J Pediatr Orthop, 30 (6): 539-43. [PMID:20733416]

22. Sidibe A, Mullier A, Chen P, Baroncini M, Boutin JA, Delagrange P, Prevot V, Jockers R. (2010) Expression of the orphan GPR50 protein in rodent and human dorsomedial hypothalamus, tanycytes and median eminence. J Pineal Res, 48 (3): 263-9. [PMID:20210849]

23. Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J. (2003) Functional activity of serotoninergic and melatoninergic systems expressed in the skin. J Cell Physiol, 196 (1): 144-53. [PMID:12767050]

24. Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A, Walker MT, Smith DJ, Pulford DJ, Muir W, Blackwood DH, Porteous DJ. (2005) Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry, 10 (5): 470-8. [PMID:15452587]

25. Zhang JC, Xie YF, Liu SJ, Dai LB, Li JP. (2010) [The expression of melatonin receptor in human hypertrophic scar]. Zhonghua Zheng Xing Wai Ke Za Zhi, 26 (3): 203-7. [PMID:20737950]

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