Contact-induced clustering of syntaxin and munc18 docks secretory granules at the exocytosis site
Open accessAbstract
Docking of secretory vesicles at the plasma membrane is a poorly understood prerequisite for exocytosis. Current models propose raft-like clusters containing syntaxin as docking receptor, but direct evidence for this is lacking. Here we provide quantitative measurements of several exocytosis proteins (syntaxin, SNAP25, munc18, munc13 and rab3) at the insulin granule release site and show that docking coincides with rapid de novo formation of syntaxin1/munc18 clusters at the nascent docking site. Formation of such clusters prevents undocking and is not observed during failed docking attempts. Overexpression of syntaxins' N-terminal Habc-domain competitively interferes with both cluster formation and successful docking. SNAP25 and munc13 are recruited to the docking site more than a minute later, consistent with munc13's reported role in granule priming rather than docking. We conclude that secretory vesicles dock by inducing syntaxin1/munc18 clustering in the target membrane, and find no evidence for preformed docking receptors.
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The interaction of Munc18 with syntaxin plays a key role in priming insulin granules for release.
“The interaction of Munc18 with syntaxin plays a key role in priming insulin granules for release (196).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [196]
The ‘Clustering of other proteins at the docking site’ section says Munc18 binds syntaxin and is required for granule docking. The Discussion distinguishes this early recruitment from the later recruitment of Munc13 and SNAP25, whose timing is consistent with a role in priming. The paper therefore assigns the Munc18–syntaxin interaction a docking role, rather than the claimed priming role. (LLM, conf=0.83)
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Experimental — accuracy not yet measuredIn INS1-cells, granule docking involves the clustering of syntaxin-1 and munc18 from a pool of freely diffusible molecules.
“In these cells, granule docking involves the clustering of the syntaxin-1 and munc18 from a pool of freely diffusible molecules.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [196]
Additional proteins required for exocytosis, including munc13 and SNAP25, are recruited to the incipient release site in INS1-cells.
“Additional proteins required for exocytosis (including munc13 and SNAP25) are then recruited to the incipient release site (196).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [196]
Granules that successfully dock are decorated with Rab3a, whereas those that do not dock lack this protein.
“Interestingly, the granules that successfully dock are decorated with Rab3a whereas those that do not dock lack this protein (196).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [196]
Only 30% of docking attempts are successful.
“Only 30% of docking attempts are successful.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [196]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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Cites
Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming
Betz, A., Thakur, P., Junge, H. J., Ashery, U., Rhee, J.-S., Scheuss, V., Rosenmund, C., Rettig, J., & Brose, N. (2001) · Neuron · doi:10.1016/s0896-6273(01)00272-0 · Cited by 425 · see citing works
Munc18-1 Promotes Large Dense-Core Vesicle Docking
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Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells
Olofsson, C. S., Göpel, S. O., Barg, S., Galvanovskis, J., Ma, X., Salehi, A., Rorsman, P., & Eliasson, L. (2002) · Pflügers Archiv · doi:10.1007/s00424-002-0781-5 · Cited by 290 · see citing works
Self-citationQuantitative analysis of the native presynaptic cytomatrix by cryoelectron tomography
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Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis
Ohara-Imaizumi, M., Fujiwara, T., Nakamichi, Y., Okamura, T., Akimoto, Y., Kawai, J., Matsushima, S., Kawakami, H., Watanabe, T., Akagawa, K., et al. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200608132 · Cited by 211 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 8
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Cited by
Sorted by citations
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
The cell biology of systemic insulin function
Tokarz, V. L., MacDonald, P. E., & Klip, A. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201802095 · Cited by 471 · see citing works
“The formation and fidelity of the SNA RE complex mediating granule docking is regulated by a number of proteins such as Munc18 and syntaxin isoforms (Gandasi and Barg, 2014; Zhu et al., 2015).”
BackgroundGlucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes
Gandasi, N. R., Yin, P., Omar-Hmeadi, M., Ottosson Laakso, E., Vikman, P., & Barg, S. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.017 · Cited by 115 · see citing works
Self-citationGandasi, N. R., Gao, R., Kothegala, L., Pearce, A., Santos, C., Acreman, S., Basco, D., Benrick, A., Chibalina, M. V., Clark, A., et al. (2024) · Diabetologia · doi:10.1007/s00125-023-06060-w · Cited by 31 · see citing works
Self-citation
- Authors
- Gandasi, N. R., & Barg, S.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Barg, Sebastian
- Venue
- Nature Communications
- Published
- 2014-05-19
- Volume
- 5
- Issue
- 1
- Pages
- 3914-3914
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2103919543
- Cited by
- 130
- References
- 6
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 11 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 14 · 2017: 18 · 2016: 12 · 2015: 13 · 2014: 4
- FWCI
- 7.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- European Foundation for the Study of Diabetes
- Barndiabetesfonden
- Novo Nordisk Fonden (NNF14OC0010001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- exocytosis, Munc18, insulin secretory granules, SNAP-25, Munc13, Rab3, membrane clustering, insulin secretion
- MeSH terms
- Animals, Cell Membrane, Exocytosis, Insulin, Secretory Vesicles, Syntaxin 1, Rats, Munc18 Proteins
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