Synaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells
Open accessAbstract
Synaptotagmin (Syt)-7, a major component of the exocytotic machinery in neurons, is also the major Syt in rodent pancreatic β-cells shown to mediate glucose-stimulated insulin secretion (GSIS). However, Syt-7’s precise exocytotic actions in β-cells remain unknown. We show that Syt-7 is abundant in human β-cells. Adenovirus–short hairpin RNA knockdown (KD) of Syt-7 in human islets reduced first- and second-phase GSIS attributed to the reduction of exocytosis of predocked and newcomer insulin secretory granules (SGs). Glucose stimulation expectedly induced Syt-7 association in a Ca2+-dependent manner with syntaxin-3 and syntaxin-1A soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes known to mediate exocytosis of newcomer and predocked SGs, respectively. However, Syt-7-KD did not disrupt SNARE complex assembly. Instead, electron microscopy analysis showed that Syt-7-KD reduced the recruitment of SGs to the plasma membrane after glucose-stimulated depletion, which could not be rescued by glucagon-like peptide 1 pretreatment. To assess the possibility that this new action of Syt-7 on SG recruitment may involve calmodulin (CaM), pretreatment of islets with CaM blocker calmidazolium showed effects very similar to those of Syt-7-KD. Syt-7 therefore plays a novel more dominant function in the replenishment of releasable SG pools in human β-cells than its previously purported role in exocytotic fusion per se.
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Syt7 is important in human β-cells for the Ca2+-dependent mobilization of secretory granules, which largely corresponds to 2nd phase insulin secretion.
“Syt7 is also important in human β-cells for the Ca2+-dependent mobilization of secretory granules (149), which largely corresponds to 2nd phase insulin secretion.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [149]
The Introduction and Discussion report that Syt-7 recruits insulin granules to replenish releasable pools in human β-cells, sustaining second-phase secretion. The Results show Ca2+-dependent Syt-7 binding to proteins involved in granule exocytosis, but do not establish that the granule mobilization itself is Ca2+-dependent; the Discussion presents a possible calmodulin-mediated recruitment mechanism as requiring further study. Our copy provides no page numbers for these passages. (LLM, conf=0.82)
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- Authors
- Dolai, S., Xie, L., Zhu, D., Liang, T., Qin, T., Xie, H., Kang, Y., Chapman, E. R., & Gaisano, H. Y.
- Affiliations
- University of Toronto (CA)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gaisano, Herbert Y.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-04-26
- Volume
- 65
- Issue
- 7
- Pages
- 1962-1976
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5384637
- OpenAlex
- W2345168168
- Cited by
- 55
- References
- 46
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 2
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP86544, MOP89889)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- synaptotagmin 7, insulin secretory granules, exocytosis, glucose-stimulated insulin secretion, pancreatic beta cells, human islets, syntaxin 3, syntaxin 1A, SNARE complex, calmodulin, calmidazolium
- MeSH terms
- Adult, Aged, Animals, Calcium, Exocytosis, Female, Glucose, Humans, Imidazoles, Insulin, Male, Middle Aged, Rats, Sprague-Dawley, Secretory Vesicles, Insulin-Secreting Cells, SNARE Proteins, Qa-SNARE Proteins, Synaptotagmins, Rats, Glucagon-Like Peptide 1
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