Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells

Teresa Buenaventura; Stavroula Bitsi; William E. Laughlin; Thomas Burgoyne; Zekun Lyu; Affiong I. Oqua; Hannah Norman; Emma R. McGlone; Andrey S. Klymchenko; Ivan R. Corrêa; Abigail Walker; Asuka Inoue; Aylin Hanyaloglu; Jak Grimes; Zsombor Koszegi; Davide Calebiro; Guy A. Rutter; Stephen R. Bloom; Ben Jones; Alejandra Tomas

doi:10.1371/journal.pbio.3000097

Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells

Teresa Buenaventura, Stavroula Bitsi, William E. Laughlin, Thomas Burgoyne, Zekun Lyu, Affiong I. Oqua, Hannah Norman, Emma R. McGlone, Andrey S. Klymchenko, Ivan R. Corrêa, Abigail Walker, Asuka Inoue, Aylin Hanyaloglu, Jak Grimes, Zsombor Koszegi, Davide Calebiro, Guy A. Rutter, Stephen R. Bloom, Ben Jones, Alejandra Tomas

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

Abstract

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in finetuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquidordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

Original language	English
Article number	e3000097
Journal	PLoS Biology
Volume	17
Issue number	8
DOIs	https://doi.org/10.1371/journal.pbio.3000097
Publication status	Published - 2019 Aug 20
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Agricultural and Biological Sciences(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pbio.3000097

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Buenaventura, T., Bitsi, S., Laughlin, W. E., Burgoyne, T., Lyu, Z., Oqua, A. I., Norman, H., McGlone, E. R., Klymchenko, A. S., Corrêa, I. R., Walker, A., Inoue, A., Hanyaloglu, A., Grimes, J., Koszegi, Z., Calebiro, D., Rutter, G. A., Bloom, S. R., Jones, B., & Tomas, A. (2019). Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells. PLoS Biology, 17(8), [e3000097]. https://doi.org/10.1371/journal.pbio.3000097

Buenaventura, T, Bitsi, S, Laughlin, WE, Burgoyne, T, Lyu, Z, Oqua, AI, Norman, H, McGlone, ER, Klymchenko, AS, Corrêa, IR, Walker, A, Inoue, A, Hanyaloglu, A, Grimes, J, Koszegi, Z, Calebiro, D, Rutter, GA, Bloom, SR, Jones, B & Tomas, A 2019, 'Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells', PLoS Biology, vol. 17, no. 8, e3000097. https://doi.org/10.1371/journal.pbio.3000097

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abstract = "The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in finetuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquidordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.",

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AU - Lyu, Zekun

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AU - McGlone, Emma R.

AU - Klymchenko, Andrey S.

AU - Corrêa, Ivan R.

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AU - Inoue, Asuka

AU - Hanyaloglu, Aylin

AU - Grimes, Jak

AU - Koszegi, Zsombor

AU - Calebiro, Davide

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AU - Bloom, Stephen R.

AU - Jones, Ben

AU - Tomas, Alejandra

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Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells

Abstract

ASJC Scopus subject areas

UN SDGs

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