Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1

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Abstract

The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

Original languageEnglish
Pages (from-to)223-240
Number of pages18
JournalBiochemical Pharmacology
Volume156
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Biased agonism
  • Cell signaling
  • G protein coupled receptors (GPCRs)
  • Glucagon-like peptide-1 receptor
  • Receptor structure-function
  • Signal transduction

Cite this

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title = "Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1",
abstract = "The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.",
keywords = "Biased agonism, Cell signaling, G protein coupled receptors (GPCRs), Glucagon-like peptide-1 receptor, Receptor structure-function, Signal transduction",
author = "Furness, {S. G.B.} and A. Christopoulos and Sexton, {P. M.} and D. Wootten",
year = "2018",
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language = "English",
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journal = "Biochemical Pharmacology",
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T1 - Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1

AU - Furness, S. G.B.

AU - Christopoulos, A.

AU - Sexton, P. M.

AU - Wootten, D.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

AB - The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

KW - Biased agonism

KW - Cell signaling

KW - G protein coupled receptors (GPCRs)

KW - Glucagon-like peptide-1 receptor

KW - Receptor structure-function

KW - Signal transduction

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