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, Patrick M Sexton

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68 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)486-497
Number of pages12
JournalMolecular Pharmacology
Issue number3
Publication statusPublished - Sep 2011


  • Allosteric Regulation
  • Amino Acid Sequence
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Mutagenesis
  • Phosphorylation
  • Polymorphism, Genetic
  • Radioligand Assay
  • Receptors, Glucagon
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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