title: The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW.
abstract: GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle "similar targets bind similar ligands", we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Anne Cathrine
authors.initials: AC
authors.lastname: Nøhr
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Shehata
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hauser
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Vignir
authors.initials: V
authors.lastname: Isberg
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Jacek
authors.initials: J
authors.lastname: Mokrosinski
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Andersen
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Daniel Sejer
authors.initials: DS
authors.lastname: Pedersen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: david.goriam@sund.ku.dk.
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: hbo@sund.ku.dk.
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism*; D019824:beta-MSH / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D044105:Receptor, Melanocortin, Type 4; D043562:Receptors, G-Protein-Coupled; D019824:beta-MSH; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones
keywords: Adrenocorticotropic hormone (ACTH); GPR139; Melanocyte stimulating hormone (MSH); Orphan GPCR; Peptide receptor; Pro-opiomelanocortin (POMC)