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GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids S L-Tryptophan and L-Phenylalanine

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GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids S L-Tryptophan and L-Phenylalanine Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2015/09/08/mol.115.100412.DC1 1521-0111/88/5/911–925$25.00 http://dx.doi.org/10.1124/mol.115.100412 MOLECULAR PHARMACOLOGY Mol Pharmacol 88:911–925, November 2015 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids s L-Tryptophan and L-Phenylalanine Changlu Liu, Pascal Bonaventure, Grace Lee, Diane Nepomuceno, Chester Kuei, Jiejun Wu, Qingqin Li, Victory Joseph, Steven W. Sutton, William Eckert, Xiang Yao, Lynn Yieh, Curt Dvorak, Nicholas Carruthers, Heather Coate, Sujin Yun, Christine Dugovic, Anthony Harrington, and Timothy W. Lovenberg Downloaded from Janssen Research & Development LLC, San Diego, California Received June 18, 2015; accepted September 4, 2015 ABSTRACT GPR139 is an orphan G-protein–coupled receptor expressed in a high-throughput screening campaign led to the identification of molpharm.aspetjournals.org the central nervous system. To identify its physiologic ligand, we a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro- measured GPR139 receptor activity from recombinant cells after N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium- treatment with amino acids, orphan ligands, serum, and tissue labeled JNJ-63533054 bound to cell membranes expressing extracts. GPR139 activity was measured using guanosine 59-O- GPR139 and could be specifically displaced by L-Trp and L-Phe. (3-[35S]thio)-triphosphate binding, calcium mobilization, and ex- Sequence alignment revealed that GPR139 is highly conserved tracellular signal–regulated kinases phosphorylation assays. across species, and RNA sequencing studies of rat and human Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) tissues indicated its exclusive expression in the brain and pituitary activated GPR139, with EC50 values in the 30- to 300-mM range, gland. Immunohistochemical analysis showed specific expression consistent with the physiologic concentrations of L-Trp and L-Phe of the receptor in circumventricular regions of the habenula and in tissues. Chromatography of rat brain, rat serum, and human septum in mice. Together, these findings suggest that L-Trp and at ASPET Journals on September 24, 2021 serum extracts revealed two peaks of GPR139 activity, which L-Phe are candidate physiologic ligands for GPR139, and we corresponded to the elution peaks of L-Trp and L-Phe. With the hypothesize that this receptor may act as a sensor to detect purpose of identifying novel tools to study GPR139 function, dynamic changes of L-Trp and L-Phe in the brain. Introduction than 30% of the drugs currently on the market target GPCRs; yet, to date, they only affect a small proportion of all known The application of modern molecular biology techniques has GPCRs. Thus, the potential for drug discovery within this field led to the identification of 865 genes in the G-protein–coupled remains enormous. For this reason, orphan GPCRs represent receptor (GPCR) family (Fredriksson et al., 2003; Fredriksson an attractive source of new targets for drug discovery re- and Schiöth, 2005). Activation of GPCRs can occur through search. About 300 GPCRs were deorphanized over the past binding of a variety of ligands, including peptides, neuro- two decades (Civelli et al., 2013). The rate of natural ligand transmitters, hormones, ions, light, pheromones, amino acids, discoveries has decreased, suggesting that the remaining amines, nucleosides, and lipids. Given the importance of orphan GPCRs may have nonclassic ligands or ligands that GPCRs in many aspects of physiology, they are among the are heretofore unanticipated by sequence homology analysis. most pursued targets for drug development (Heng et al., 2013; One such orphan, GPR139 (or GPRg1 or GPCR12) was first Lundstrom and Chiu, 2005; Overington et al., 2006). More identified as a Rhodopsin family GPCR with exclusive expres- sion in the central nervous system (Gloriam et al., 2005; Changlu Liu and Pascal Bonaventure contributed equally to this work. Matsuo et al., 2005). Its closest homolog, GPR142, however, is dx.doi.org/10.1124/mol.115.100412. s This article has supplemental material available at molpharm. expressed primarily in the pancreas and other peripheral aspetjournals.org. tissues (Susens et al., 2006). In situ hybridization experiments ABBREVIATIONS: CHO, Chinese hamster ovary cells; DMEM, Dulbecco’s modified Eagle’s medium; ERK, extracellular signal–regulated kinases; FBS, fetal bovine serum; GPCR, G-protein–coupled receptor; GPR139, GTEx, genotype-tissue expression; GTPgS, guanosine 59-O-(3-thio)- triphosphate; HBSS, Hanks’ balanced salt solution; HEK, human embryonic kidney; HPLC, high-performance liquid chromatography; JNJ- 63533054, [(S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]; JNJ-63770044, (R)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide)]; LP-360924, (2-((4-methoxy-6-((3-methoxypropyl)amino)-1,3,5-triazin-2-yl)amino)-4-phenylthiazol-5-yl)(4-(pyrimidin-2-yl)piperazin-1-yl) methanone; LP-471756, 4-cyclohexyl-N-(o-tolyl)benzenesulfonamide; LP-114958, 3-benzyl-N,5-dicyclohexyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7- amine); PBS, phosphate-buffered saline; PCPA, p-chlorophenylalanine; PCR, polymerase chain reaction; TCO-9311, (3,5-dimethoxybenzoic acid 2-[(1-naphthalenylamino)carbonyl]hydrazide). 911 912 Liu et al. in mouse brain showed that GPR139 mRNA is abundantly bromo-5-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide expressed in the septum, caudate, habenula, zona incerta, and was used to prepare [3H]JNJ-63533054 (24.7 Ci/mmol) via reduction of medial mammillary nucleus (Matsuo et al., 2005; Susens the bromide with tritium through a contract with Moravek Biochemicals 3 et al., 2006). The receptor has been reported to be coupled (Brea, CA). The radiochemical purity of [ H]JNJ-63533054 was with Gq and constitutively active when recombinantly determined to be 99.1% by high-performance liquid chromatography (HPLC) analysis with radioactive flow detection. TC-O9311 (3,5- expressed in mammalian cells (Matsuo et al., 2005). To date, dimethoxybenzoic acid 2-[(1-naphthalenylamino)carbonyl]hydrazide) three groups have reported surrogate small molecules for was purchased from Tocris Bioscience (Bristol, UK). [35S]-GTPgS GPR139. Shi et al. (2011) identified a series of benzohydra- (1250 Ci/mmol) was purchased from PerkinElmer (Waltham, MA). zides as potent and selective surrogate agonists for GPR139; Molecular Cloning of GPR139 from Different Species. the most potent compound is also known as TCO-9311 (3,5- GPR139 from human, monkey, dog, mouse, rat, chicken, turtle, and dimethoxybenzoic acid 2-[(1-naphthalenylamino)carbonyl] frog were cloned from respective brain cDNAs. A human GPR139 hydrazide). Hu et al. (2009) also identified surrogate agonists gene fragment was identified by blast (tblastn) search of the human (including LP-360924, (2-((4-methoxy-6-((3-methoxypropyl)amino)- genomic sequence using human somatostatin 4 receptor as the tem- 9 9 1,3,5-triazin-2-yl)amino)-4-phenylthiazol-5-yl)(4-(pyrimidin-2- plate. The 5 end and 3 end of the human GPR139 were identified by yl)piperazin-1-yl)methanone) and antagonists (LP-471756 rapid amplification of cDNA end using the human fetal brain cDNA as the template. The 59 and 39 ends and the genomic sequences of 4-cyclohexyl-N-(o-tolyl)benzenesulfonamide and LP-114958 human GPR139 were used to assemble the full-length coding region. Downloaded from 3-benzyl-N,5-dicyclohexyl-3H-[1,2,3]triazolo[4,5-day]pyrimihdin- The DNA coding regions for GPR139 from other species were 7-amine) for GPR139. More recently, Wang et al. (2015) identified using the predicted human GPR139 protein sequence to identified five small-molecule antagonists representing four blast search (tblastn) the genomic sequences from respective species. different scaffolds. All these compounds showed reasonable To clone the GPR139 cDNAs for recombinant expression, specific potency, but little to no selectivity data were reported. During primers were used to amplify the GPR139 coding regions from these the preparation of this article, Isberg and colleagues (2014) species using the respective brain cDNAs as the templates. Primers disclosed a pharmacophore model based on known surro- for human (forward: 59 ACG TCA GAA TTC GCC ACC ATG GAG CAC molpharm.aspetjournals.org ACG CAC GCC CAC CT 39; reverse: 59 ATG TCA GCG GCC GCT CAC gate GPR139 agonists to propose L-tryptophan (L-Trp) and GGG GAT ACT TTT ATA GGT TTT CCA TTT TTG TCA TAC TG 39), L-phenylalanine (L-Phe) as putative endogenous ligands for monkey (forward: 59 ACG TCA GGT ACC GCC ACC ATG GAG CAC GPR139. ACG CAC GCC CAC CTC GCA GCC AAC A 39; reverse: 59 ATG TCA The goal of the present study was to identify the physio- GCG GCC GCT CAC GGG GAT ACT TTT ATA GGT TTT CCA TTT logic ligand for GPR139. We measured GPR139 receptor ac- TTG TCA TAC TGG TAC 39), dog (forward: 59GTC TCA GGA TCC tivity in recombinant cells after treatment with various amino GCC ACC ATG GAG CAC ACG CAC GCC CAC CTC GCC GCC 39; acids and orphan ligands. GPR139 activity in recombinant reverse: 59 CTA CTA CTA CTA GCG GCC GCT CAC GGG GAT ACT systems was measured using guanosine 59-O-(3-[35S]thio)- TTT ATA GGT TTT CCA TT 39), mouse (forward: 59 ACT AGA GAA 35 triphosphate ([ S]GTPgS) binding, calcium mobilization, TTC GCC ACC ATG GAG CAC ACG CAC GCC CAC CTC 39; reverse: at ASPET Journals on September 24, 2021 and extracellular signal–regulated kinases (ERK) phosphor- 59 ACT AGA GCG GCC GCT CAC GGG GAT ACT TTT ATA GGC TTT ylation. Chromatography of rat serum, rat brain, and human CCA TG 39), rat (forward: 59 ACT AGA GAA TTC GCC ACC ATG GAG 9 9 serum extracts was used to confirm the identity of the natural CAC ACG CAC GCC CAC CTC GCT GCG AAT AG 3 ; reverse: 5 ACT AGA GCG GCC GCT CAC GGG GAT ACT TTT ATA GGC TTC CCA ligands.
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