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Molecular Pharmacology

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Research ArticleArticle

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids 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
Molecular Pharmacology November 2015, 88 (5) 911-925; DOI: https://doi.org/10.1124/mol.115.100412
Changlu Liu
Janssen Research & Development LLC, San Diego, California
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Pascal Bonaventure
Janssen Research & Development LLC, San Diego, California
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Grace Lee
Janssen Research & Development LLC, San Diego, California
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Diane Nepomuceno
Janssen Research & Development LLC, San Diego, California
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Chester Kuei
Janssen Research & Development LLC, San Diego, California
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Jiejun Wu
Janssen Research & Development LLC, San Diego, California
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Qingqin Li
Janssen Research & Development LLC, San Diego, California
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Victory Joseph
Janssen Research & Development LLC, San Diego, California
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Steven W. Sutton
Janssen Research & Development LLC, San Diego, California
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William Eckert
Janssen Research & Development LLC, San Diego, California
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Xiang Yao
Janssen Research & Development LLC, San Diego, California
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Lynn Yieh
Janssen Research & Development LLC, San Diego, California
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Curt Dvorak
Janssen Research & Development LLC, San Diego, California
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Nicholas Carruthers
Janssen Research & Development LLC, San Diego, California
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Heather Coate
Janssen Research & Development LLC, San Diego, California
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Sujin Yun
Janssen Research & Development LLC, San Diego, California
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Christine Dugovic
Janssen Research & Development LLC, San Diego, California
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Anthony Harrington
Janssen Research & Development LLC, San Diego, California
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Timothy W. Lovenberg
Janssen Research & Development LLC, San Diego, California
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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-[35S]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 across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that l-Trp and l-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of l-Trp and l-Phe in the brain.

Footnotes

    • Received June 18, 2015.
    • Accepted September 4, 2015.
  • Changlu Liu and Pascal Bonaventure contributed equally to this work.

  • dx.doi.org/10.1124/mol.115.100412.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (5)
Molecular Pharmacology
Vol. 88, Issue 5
1 Nov 2015
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Research ArticleArticle

GPR139 Is Activated by 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
Molecular Pharmacology November 1, 2015, 88 (5) 911-925; DOI: https://doi.org/10.1124/mol.115.100412

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Research ArticleArticle

GPR139 Is Activated by 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
Molecular Pharmacology November 1, 2015, 88 (5) 911-925; DOI: https://doi.org/10.1124/mol.115.100412
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