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Molecular Pharmacology

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Research ArticleArticle

GPR83 Engages Endogenous Peptides from Two Distinct Precursors to Elicit Differential Signaling

Seshat M. Mack, Ivone Gomes, Amanda K. Fakira, Mariana Lemos Duarte, Achla Gupta, Lloyd Fricker and Lakshmi A. Devi
Molecular Pharmacology July 2022, 102 (1) 29-38; DOI: https://doi.org/10.1124/molpharm.122.000487
Seshat M. Mack
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Ivone Gomes
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Amanda K. Fakira
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Mariana Lemos Duarte
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Achla Gupta
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Lloyd Fricker
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Lakshmi A. Devi
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (S.M.M., I.G., A.K.F., M.L.D., A.G., L.A.D.) and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York (L.F.)
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Abstract

PEN is an abundant neuropeptide that activates G protein-coupled receptor 83 (GPR83), which is considered a novel therapeutic target due to its roles in regulation of feeding-, reward-, and anxiety-related behaviors. The major form of PEN in the brain is 22 residues in length. Previous studies have identified shorter forms of PEN in mouse brain and neuroendocrine cells; these shorter forms were named PEN18, PEN19, and PEN20, with the number reflecting the length of the peptide. The C-terminal five residues of PEN20 are identical to the C-terminus of a procholecystokinin (proCCK)-derived peptide, named proCCK56-62, that is present in mouse brain. ProCCK56-62 is highly conserved across species, although it has no homology to the bioactive cholecystokinin domain. ProCCK56-62 and a longer form, proCCK56-63, were tested for their ability to engage GPR83. Both peptides bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis. Interestingly, the shorter PEN peptides, ProCC56-62 and ProCCK56-63, differentially activate signal transduction pathways. Whereas PEN22 and PEN20 facilitate receptor coupling to Gαi, PEN18, PEN19, and ProCCK peptides facilitate coupling to Gαs. Furthermore, the ProCCK peptides exhibit dose-dependent Gα subtype selectivity in that they facilitate coupling to Gαs at low concentrations and Gαi at high concentrations. These data demonstrate that peptides derived from two distinct peptide precursors can differentially activate GPR83 and that GPR83 exhibits Gα subtype preference depending on the nature and concentration of the peptide. These results are consistent with the emerging idea that endogenous neuropeptides function as biased ligands.

SIGNIFICANCE STATEMENT We found that peptides derived from procholecystokinin (proCCK) bind and activate G protein-coupled receptor 83, which is known to bind peptides derived from proSAAS. Different forms of the proCCK- and proSAAS-derived peptides show biased agonism, activating Gαs or Gαi depending on the length of the peptide and/or its concentration.

Footnotes

    • Received January 4, 2022.
    • Accepted May 3, 2022.
  • This research was funded by National Institutes of Health grants: National Institute on Drug Abuse [Grant R01-DA008863], National Institute of Neurologic Disorders and Stroke [Grant R01-NS026880], and National Center for Advancing Translational Sciences [Grant 1R03-TR003647-01] (to L.A.D.) and diversity supplement [R01-DA008863S] (to S.M.M.).

  • The authors do not have any conflicts of interest to disclose.

  • ↵1 Current affiliation: Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, New Jersey.

  • ↵2 S.M.M. and I.G. contributed equally to this work.

  • https://doi.org/10.1124/molpharm.122.000487.

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

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 102 (1)
Molecular Pharmacology
Vol. 102, Issue 1
1 Jul 2022
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Research ArticleArticle

Peptide-Mediated Differential Signaling at GPR83

Seshat M. Mack, Ivone Gomes, Amanda K. Fakira, Mariana Lemos Duarte, Achla Gupta, Lloyd Fricker and Lakshmi A. Devi
Molecular Pharmacology July 1, 2022, 102 (1) 29-38; DOI: https://doi.org/10.1124/molpharm.122.000487

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Research ArticleArticle

Peptide-Mediated Differential Signaling at GPR83

Seshat M. Mack, Ivone Gomes, Amanda K. Fakira, Mariana Lemos Duarte, Achla Gupta, Lloyd Fricker and Lakshmi A. Devi
Molecular Pharmacology July 1, 2022, 102 (1) 29-38; DOI: https://doi.org/10.1124/molpharm.122.000487
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