Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide and oxyntomodulin that are biased towards pERK1/2 relative to cAMP (when compared to GLP-1 and exendin-4), also stimulated pERK1/2 activity in the cytosol. This compartmentalisation of ERK1/2 signalling was reliant on receptor internalisation, with restriction of receptor localisation to the plasma membrane limiting ERK1/2 signalling to the cytosol. Thus, this study implicates a role of receptor internalisation in spatiotemporal control of ERK1/2 signalling that may contribute to GLP-1R biased agonism.

Original languageEnglish
Pages (from-to)406-419
Number of pages14
JournalBiochemical Pharmacology
Volume156
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Biased agonism
  • Glucagon-like peptide 1 receptor
  • Internalisation
  • Receptor trafficking
  • Spatiotemporal signalling

Cite this

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title = "Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists",
abstract = "The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide and oxyntomodulin that are biased towards pERK1/2 relative to cAMP (when compared to GLP-1 and exendin-4), also stimulated pERK1/2 activity in the cytosol. This compartmentalisation of ERK1/2 signalling was reliant on receptor internalisation, with restriction of receptor localisation to the plasma membrane limiting ERK1/2 signalling to the cytosol. Thus, this study implicates a role of receptor internalisation in spatiotemporal control of ERK1/2 signalling that may contribute to GLP-1R biased agonism.",
keywords = "Biased agonism, Glucagon-like peptide 1 receptor, Internalisation, Receptor trafficking, Spatiotemporal signalling",
author = "Fletcher, {Madeleine M.} and Halls, {Michelle L.} and Peishen Zhao and Lachlan Clydesdale and Arthur Christopoulos and Sexton, {Patrick M.} and Denise Wootten",
year = "2018",
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T1 - Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists

AU - Fletcher, Madeleine M.

AU - Halls, Michelle L.

AU - Zhao, Peishen

AU - Clydesdale, Lachlan

AU - Christopoulos, Arthur

AU - Sexton, Patrick M.

AU - Wootten, Denise

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide and oxyntomodulin that are biased towards pERK1/2 relative to cAMP (when compared to GLP-1 and exendin-4), also stimulated pERK1/2 activity in the cytosol. This compartmentalisation of ERK1/2 signalling was reliant on receptor internalisation, with restriction of receptor localisation to the plasma membrane limiting ERK1/2 signalling to the cytosol. Thus, this study implicates a role of receptor internalisation in spatiotemporal control of ERK1/2 signalling that may contribute to GLP-1R biased agonism.

AB - The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide and oxyntomodulin that are biased towards pERK1/2 relative to cAMP (when compared to GLP-1 and exendin-4), also stimulated pERK1/2 activity in the cytosol. This compartmentalisation of ERK1/2 signalling was reliant on receptor internalisation, with restriction of receptor localisation to the plasma membrane limiting ERK1/2 signalling to the cytosol. Thus, this study implicates a role of receptor internalisation in spatiotemporal control of ERK1/2 signalling that may contribute to GLP-1R biased agonism.

KW - Biased agonism

KW - Glucagon-like peptide 1 receptor

KW - Internalisation

KW - Receptor trafficking

KW - Spatiotemporal signalling

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DO - 10.1016/j.bcp.2018.09.003

M3 - Article

VL - 156

SP - 406

EP - 419

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -