Disease relevance of GPR50

• The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism [1].
• The influenza virus matrix protein (M1) possesses a cysteine and histidine (CCHH) motif in the helix 9 (H9) and adjacent region ((148)CATCEQIADSQHRSH(162)) [2].

Psychiatry related information on GPR50

• Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor [3].
• Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population [4].

High impact information on GPR50

• The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization [5].
• 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 [5].
• The melatonin-related receptor, despite sharing considerable amino acid sequence identity with melatonin receptors, does not bind melatonin and is currently an orphan G protein-coupled receptor [6].
• The subsequent testing of a "reverse" chimeric receptor in which sequences encoding transmembrane domains 4 and 6 of the melatonin-related receptor were replaced by the corresponding melatonin mt(1) receptor sequences identified specific 2-[(125)I]iodomelatonin binding and melatonin-mediated modulation of cyclic AMP levels [6].
• Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels [1].

Biological context of GPR50

• Assignment of the melatonin-related receptor to human chromosome X (GPR50) and mouse chromosome X (Gpr50) [7].
• Unusual features of the protein encoded by H9 include a lack of N-linked glycosylation sites and a carboxyl tail >300 amino acids long [8].
• A melatonin-related receptor was cloned from an ovine genomic library [9].
• Exon 1 and exon 2 of the ovine melatonin-related receptor encode a protein of 575 amino acids which is 73.8% homologous to the human melatonin-related receptor and shows 40.9% homology with the ovine Mel1a melatonin receptor [9].
• However, the lethal phenotype of the Ala(155) mutation shows that the H9 region of M1 provides some other critical function(s) in virus replication [2].

Anatomical context of GPR50

• H9 mRNA is expressed in hypothalamus and pituitary, suggesting that the encoded receptor and its natural ligand are involved in neuroendocrine function [8].
• H9 transiently expressed in COS-1 cells did not bind [125I]melatonin or [3H]melatonin [8].
• Photoperiodic regulation of cellular retinoic acid-binding protein 1, GPR50 and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster [10].
• Inhibition by glucosamine of myristoylation in human H9 lymphocytes and rat liver cells [11].

Associations of GPR50 with chemical compounds

• Thus, the mutation of glycine 20 to threonine, the corresponding H9 residue, severely reduced the receptor's affinity for melatonin [12].
• Furthermore, expression of the ovine melatonin-related receptor is shown to be coincident with Mel1a and 2-[125I]iodomelatonin binding in the pituitary and serotonin N-acetyl transferase (arylalkylamine N-acetyl transferase, AANAT) expression in the retina [9].
• Glucosamine also inhibited incorporation of radiolabelled myristic acid into H9 cell proteins in vivo [11].

Other interactions of GPR50

• To delineate domains of high affinity melatonin receptors that are essential for melatonin binding, we generated chimeras between the human Mel1a melatonin receptor and the melatonin-related orphan H9 receptor [12].

Analytical, diagnostic and therapeutic context of GPR50

• Both genes were found to be X-linked: radiation hybrid mapping revealed that the human H9 gene (GPR50) is localized to Xq28 [7].
• Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization studies revealed expression of the ovine melatonin-related receptor in the hypothalamus, pituitary, retina and retinal pigment epithelium [9].

References