National Academy of Sciences, Proceedings of the National Academy of Sciences, 32(112), p. 9996-10001, 2015
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Significance The present study shows that glucagon-like peptide-1 (GLP-1) potentiates insulin release by inducing the PKA-mediated phosphorylation of synaptotagmin-7 in pancreatic β-cells, thereby documenting that the hormone GLP-1 acts by directly enhancing Ca 2+ -triggered insulin exocytosis. PKA phosphorylates synaptotagmin-7 at a single serine residue in the linker between the synaptotagmin-7 transmembrane region and its C-terminal C 2 domains that bind Ca 2+ ; accordingly, PKA phosphorylation of synaptotagmin-7 enhances insulin secretion without changing the Ca 2+ dependence of secretion. The study documents that the efficacy of a synaptotagmin can be modulated by phosphorylation and highlights the importance of synaptotagmin-7 in mediating glucose-stimulated insulin secretion. Given the importance of enhancing β-cell function in the treatment of diabetes, the present findings may offer new pathways for developing future therapeutic strategies.