Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells. 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. PLoS biology, 17(8):e3000097, 2019.
doi  abstract   bibtex   
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.
@article{buenaventura_agonist-induced_2019,
	title = {Agonist-induced membrane nanodomain clustering drives {GLP}-1 receptor responses in pancreatic beta cells},
	volume = {17},
	issn = {1545-7885},
	doi = {10.1371/journal.pbio.3000097},
	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.},
	language = {eng},
	number = {8},
	journal = {PLoS biology},
	author = {Buenaventura, Teresa and Bitsi, Stavroula and Laughlin, William E. and Burgoyne, Thomas and Lyu, Zekun and Oqua, Affiong I. and Norman, Hannah and McGlone, Emma R. and Klymchenko, Andrey S. and Corrêa, Ivan R. and Walker, Abigail and Inoue, Asuka and Hanyaloglu, Aylin and Grimes, Jak and Koszegi, Zsombor and Calebiro, Davide and Rutter, Guy A. and Bloom, Stephen R. and Jones, Ben and Tomas, Alejandra},
	year = {2019},
	pmid = {31430273},
	pmcid = {PMC6716783},
	keywords = {Animals, CHO Cells, Cell Membrane, Cluster Analysis, Cricetulus, Cyclic AMP, Diabetes Mellitus, Type 2, Endocytosis, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Lipoylation, Signal Transduction},
	pages = {e3000097}
}

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