Synaptotagmin-7 phosphorylation mediates GLP-1–dependent potentiation of insulin secretion from β-cells
Open accessAbstract
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.
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Many potentiators of insulin secretion exert a direct effect on late steps of exocytosis in addition to stimulating β-cell electrical activity.
“Many potentiators of insulin secretion exert a direct effect on late steps of exocytosis in addition to stimulating β-cell electrical activity.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [735]
The Significance section reports that GLP-1 directly enhances Ca²⁺-triggered insulin exocytosis, supporting the claim for one potentiator. The Discussion also describes GLP-1 increasing calcium through Epac2, but it does not establish that many potentiators both act on late exocytotic steps and stimulate β-cell electrical activity. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSomatostatin's inhibitory effect may involve dephosphorylation of the same serine residue in Syt7 that is phosphorylated in the presence of GLP-1.
“There is some evidence that somatostatin’s inhibitory effect on exocytosis is mediated by activation of the protein phosphatase calcineurin (543), possibly by dephosphorylation of the same serine residue in Syt7 that is phosphorylated in the presence of GLP-1 (735).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [735]
The Results identify serine-103 as the Syt7 residue phosphorylated in response to GLP-1 signaling, and the Discussion links that phosphorylation to enhanced exocytosis. The paper does not address whether somatostatin inhibits exocytosis by dephosphorylating that residue, so it supports only the GLP-1 side of the proposed mechanism. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGLP-1 stimulates exocytosis by cAMP-dependent activation of PKA, which phosphorylates synaptotagmin-7 at serine-103.
“For example, GLP-1 stimulates exocytosis via Epac2 (170) and by cAMP-dependent activation of PKA, which phosphorylates synaptotagmin-7 at serine-103 (735).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [735]
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Pancreatic regulation of glucose homeostasis.
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Self-citationPancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
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Self-citationSynaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells
Dolai, S., Xie, L., Zhu, D., Liang, T., Qin, T., Xie, H., Kang, Y., Chapman, E. R., & Gaisano, H. Y. (2016) · Diabetes · doi:10.2337/db15-1436 · Cited by 55 · see citing works
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- Authors
- Wu, B., Wei, S., Petersen, N., Ali, Y., Wang, X., Bacaj, T., Rorsman, P., Hong, W., Südhof, T. C., & Han, W.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Howard Hughes Medical Institute (US)
- Churchill Hospital (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-07-27
- Volume
- 112
- Issue
- 32
- Pages
- 9996-10001
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4538675
- OpenAlex
- W1702317583
- Cited by
- 76
- References
- 7
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 2
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (MH086403)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- synaptotagmin 7, glucagon-like peptide-1, insulin secretion, pancreatic beta cells, protein kinase A, calcium-triggered exocytosis, glucose homeostasis, type 2 diabetes, GLP-1 receptor agonists, phosphomimetic mutant
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Insulin Secretion, Cyclic AMP, Amino Acid Sequence, Animals, Exocytosis, Colforsin, Glucose, Humans, Insulin, Molecular Sequence Data, Mutation, Peptides, Phosphorylation, Phosphoserine, Venoms, Conserved Sequence, Cyclic AMP-Dependent Protein Kinases, Receptors, Glucagon, Mice, Knockout, Evolution, Molecular, Insulin-Secreting Cells, Synaptotagmins, Rats, Glucagon-Like Peptide 1, HEK293 Cells
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