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

Metabolism and Systems Science

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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 fine-tuning 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 liquid-ordered 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
Pages (from-to)	e3000097
Journal	PLoS Biology
Volume	17
Issue number	8
DOIs	https://doi.org/10.1371/journal.pbio.3000097
Publication status	Published - 20 Aug 2019

ASJC Scopus subject areas

General Neuroscience
General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology
General Agricultural and Biological Sciences

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10.1371/journal.pbio.3000097Licence: Creative Commons: Attribution (CC BY)

Beunaventura_et_al_Agonist-induced_membrane_nanodomain_clustering_drives_GLP-1_receptor_responses_in_pancreatic_beta_cells_PLOS_Biology_
Buenaventura T, Bitsi S, Laughlin WE, Burgoyne T, Lyu Z, Oqua AI, et al. (2019) Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells. PLoS Biol 17(8): e3000097. https://doi.org/10.1371/journal.pbio.3000097
Final published version, 4.51 MBLicence: Creative Commons: Attribution (CC BY)

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000097Licence: Creative Commons: Attribution (CC BY)

Cite this

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

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title = "Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells",

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 fine-tuning 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 liquid-ordered 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.",

author = "Teresa Buenaventura and Stavroula Bitsi and Laughlin, {William E} and Thomas Burgoyne and Zekun Lyu and Oqua, {Affiong I} and Hannah Norman and McGlone, {Emma R} and Klymchenko, {Andrey S} and Corr{\^e}a, {Ivan R} and Abigail Walker and Asuka Inoue and Aylin Hanyaloglu and Jak Grimes and Zsombor Koszegi and Davide Calebiro and Rutter, {Guy A} and Bloom, {Stephen R} and Ben Jones and Alejandra Tomas",

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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, pp. e3000097. https://doi.org/10.1371/journal.pbio.3000097

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AU - Buenaventura, Teresa

AU - Bitsi, Stavroula

AU - Laughlin, William E

AU - Burgoyne, Thomas

AU - Lyu, Zekun

AU - Oqua, Affiong I

AU - Norman, Hannah

AU - McGlone, Emma R

AU - Klymchenko, Andrey S

AU - Corrêa, Ivan R

AU - Walker, Abigail

AU - Inoue, Asuka

AU - Hanyaloglu, Aylin

AU - Grimes, Jak

AU - Koszegi, Zsombor

AU - Calebiro, Davide

AU - Rutter, Guy A

AU - Bloom, Stephen R

AU - Jones, Ben

AU - Tomas, Alejandra

PY - 2019/8/20

Y1 - 2019/8/20

N2 - 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 fine-tuning 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 liquid-ordered 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.

AB - 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 fine-tuning 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 liquid-ordered 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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SP - e3000097

JO - PLoS Biology

JF - PLoS Biology

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

Abstract

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