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Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 06 November 2012, Vol.109(45), pp.18607-12
Main Author: Harikumar, Kaleeckal G
Other Authors: Wootten, Denise , Pinon, Delia I , Koole, Cassandra , Ball, Alicja M , Furness, Sebastian G B , Graham, Bim , Dong, Maoqing , Christopoulos, Arthur , Miller, Laurence J , Sexton, Patrick M
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; PMID: 23091034 Version:1 ; DOI: 10.1073/pnas.1205227109
Link: http://pubmed.gov/23091034
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recordid: medline23091034
title: Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery
format: Article
creator:
  • Harikumar, Kaleeckal G
  • Wootten, Denise
  • Pinon, Delia I
  • Koole, Cassandra
  • Ball, Alicja M
  • Furness, Sebastian G B
  • Graham, Bim
  • Dong, Maoqing
  • Christopoulos, Arthur
  • Miller, Laurence J
  • Sexton, Patrick M
subjects:
  • Protein Multimerization -- Drug Effects
  • Receptors, Glucagon -- Agonists
  • Signal Transduction -- Drug Effects
  • Small Molecule Libraries -- Pharmacology
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 06 November 2012, Vol.109(45), pp.18607-12
description: The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was
language: eng
source:
identifier: E-ISSN: 1091-6490 ; PMID: 23091034 Version:1 ; DOI: 10.1073/pnas.1205227109
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleGlucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery
creatorHarikumar, Kaleeckal G ; Wootten, Denise ; Pinon, Delia I ; Koole, Cassandra ; Ball, Alicja M ; Furness, Sebastian G B ; Graham, Bim ; Dong, Maoqing ; Christopoulos, Arthur ; Miller, Laurence J ; Sexton, Patrick M
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subjectProtein Multimerization -- Drug Effects ; Receptors, Glucagon -- Agonists ; Signal Transduction -- Drug Effects ; Small Molecule Libraries -- Pharmacology
descriptionThe glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast,...
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descriptionThe glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast,...
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abstractThe glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast,...
doi10.1073/pnas.1205227109
pmid23091034
date2012-11-06