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

Molecular Pharmacology
Changlu LiuTimothy W Lovenberg

Abstract

GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding, calcium mobilization, and extracellular signal-regulated kinases phosphorylation assays. Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) activated GPR139, with EC50 values in the 30- to 300-μM range, consistent with the physiologic concentrations of L-Trp and L-Phe in tissues. Chromatography of rat brain, rat serum, and human serum extracts revealed two peaks of GPR139 activity, which corresponded to the elution peaks of L-Trp and L-Phe. With the purpose of identifying novel tools to study GPR139 function, a high-throughput screening campaign led to the identification of a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium-labeled JNJ-63533054 bound to cell membranes expressing GPR139 and could be specifically displaced by L-Trp and L-Phe. Sequence alignment revealed that GPR139 is highly conserved ...Continue Reading

References

Oct 3, 2003·The Journal of Biological Chemistry·Changlu LiuTimothy W Lovenberg
Feb 3, 2005·Molecular Pharmacology·Robert Fredriksson, Helgi B Schiöth
Apr 23, 2005·Biochemical and Biophysical Research Communications·Ayako MatsuoYasufumi Shigeyoshi
Nov 8, 2006·British Journal of Pharmacology·R ZucchiD K Grandy
Dec 2, 2006·Nature Reviews. Drug Discovery·John P OveringtonAndrew L Hopkins
Jun 3, 2008·Nature Methods·Ali MortazaviBarbara Wold
Jun 16, 2009·Journal of Biomolecular Screening·Liaoyuan A HuQingyun Liu
Sep 1, 2009·Neuroscience and Biobehavioral Reviews·B Y Silber, J A J Schmitt
Mar 23, 2010·Toxicologic Pathology·Jeffrey A KramerAlan G E Wilson
Jun 19, 2010·Nature Reviews. Neuroscience·Okihide Hikosaka
Dec 17, 2010·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Georg M SingewaldKarl Ebner
Oct 2, 2012·Annual Review of Pharmacology and Toxicology·Olivier CivelliHelgi B Schiöth
May 30, 2013·Nature Genetics·UNKNOWN GTEx Consortium
May 16, 2014·Journal of Chemical Information and Modeling·Vignir IsbergDavid E Gloriam
Apr 14, 2011·ACS Medicinal Chemistry Letters·Feng ShiGarrick Smith
Aug 22, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yun-Wei A HsuEric E Turner
Aug 27, 2014·Nature Neuroscience·Christophe D ProulxRoberto Malinow
Jun 2, 2015·Acta Pharmacologica Sinica·Jia WangMing-wei Wang
Sep 24, 2015·ACS Medicinal Chemistry Letters·Curt A DvorakNicholas I Carruthers

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Citations

Jul 26, 2016·Frontiers in Cellular Neuroscience·Kirsten Bayer AndersenGunnar P H Dietz
Jul 22, 2008·European Journal of Pharmacology·Wen JiangRobin L Thurmond
Jul 25, 2006·European Journal of Pharmacology·Naoto AdachiTatsuru Arai
Jun 5, 2007·European Journal of Pharmacology·Md Ashequr RahmanChiaki Kamei
Nov 4, 2016·Journal of Receptor and Signal Transduction Research·Michiko MurakoshiFutoshi Nara
Dec 20, 2016·Nature Chemical Biology·Tony NgoNicola J Smith
Aug 17, 2019·Science·Dandan WangKirill A Martemyanov
Dec 17, 2019·Alcoholism, Clinical and Experimental Research·Scott EdwardsKatie Witkiewitz
Jun 25, 2020·The Journal of Biological Chemistry·Hannah M StovekenKirill A Martemyanov
Mar 31, 2018·Frontiers in Pharmacology·Diane NepomucenoPascal Bonaventure
Feb 19, 2019·Pharmacology Research & Perspectives·Lien WangChanglu Liu
May 28, 2019·Basic & Clinical Pharmacology & Toxicology·Line VedelHans Bräuner-Osborne
Apr 10, 2020·Nature Reviews. Neuroscience·Hailan HuYan Yang
Apr 27, 2017·Scientific Reports·Anne Cathrine NøhrDavid E Gloriam
Apr 6, 2019·Frontiers in Pharmacology·James R ShoblockPascal Bonaventure
Mar 9, 2019·Scientific Reports·Anne Cathrine NøhrHans Bräuner-Osborne
Jun 13, 2020·European Journal of Pharmacology·Lien WangPascal Bonaventure
Jan 23, 2021·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Maria DaoKirill A Martemyanov
Mar 12, 2021·Scientific Reports·Nisa RoyIshwar Parhar
Jul 13, 2021·Frontiers in Behavioral Neuroscience·Young-A Lee, Yukiori Goto
Dec 22, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Mohaddeseh Sadat AlaviAli Roohbakhsh

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