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Molecular Pharmacology

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Research ArticleArticle

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Laurence J. Miller, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 2011, 80 (3) 486-497; DOI: https://doi.org/10.1124/mol.111.072884
Cassandra Koole
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Denise Wootten
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John Simms
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Celine Valant
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Laurence J. Miller
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Arthur Christopoulos
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Patrick M. Sexton
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This article has a correction. Please see:

  • Correction to “Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation” - July 01, 2012

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1–37) and truncated (7–37) forms of GLP-1 that can exist in an amidated form (GLP-1(1–36)NH2 and GLP-1(7–36)NH2) and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms (SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellular signal-regulated kinase 1/2 phosphorylation, and intracellular Ca2+ mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligand- and pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the Met149 receptor variant. At the Met149 variant, there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the Cys333 variant, peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the Met149 receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was funded in part by the National Health and Medical Research Council (NHMRC) of Australia [Grants 519461, 1002180]; and by an NHMRC Australian Principal Research Fellowship (to P.M.S.) and a Senior Research Fellowship (to A.C.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072884.

  • ABBREVIATIONS:

    GLP-1R
    glucagon-like peptide-1 receptor
    SNP
    single nucleotide polymorphism
    DMEM
    Dulbecco's modified Eagle's medium
    ERK
    extracellular signal-regulated kinase
    FBS
    Fetal bovine serum
    CHO
    Chinese hamster ovary
    BSA
    bovine serum albumin
    compound 2
    6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline.

  • Received April 11, 2011.
  • Accepted May 26, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Laurence J. Miller, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 1, 2011, 80 (3) 486-497; DOI: https://doi.org/10.1124/mol.111.072884

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Research ArticleArticle

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Laurence J. Miller, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 1, 2011, 80 (3) 486-497; DOI: https://doi.org/10.1124/mol.111.072884
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