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Abstract
Type 2 diabetes is marked by deterioration in pancreatic β-cell function. SNARE-proteins are crucial for the fusion of insulin granules with the plasma membrane, a prerequisite for insulin secretion. The aim of this thesis has been to investigate the exocytotic process in β-cells with a specific focus on the function and significance of the two SNARE-proteins SNAP-25 and syntaxin 1.
SNAP-25 and syntaxin 1 was discovered to be situated in clusters along the plasma membrane. Immunoneutralization of syntaxin 1 and SNAP-25 resulted in a strongly reduced exocytotic response of primed granules in close association with the voltage-dependent calcium channels.
Cholesterol is an essential component of the plasma membrane. Desorption of cholesterol from the plasma membrane in β-cells were accompanied with an overall reduction in the response of β-cells, from insulin secretion to exocytosis. We believe this is due to disturbance of a basic mechanism. Indeed, we found that SNAP-25 migrated from the plasma membrane out to the cytosol.
The stimulating effect of cAMP on insulin secretion is implemented through different pathways. One pathway is through cAMP-GEFII and its downstream affector RIM2. We show that SNAP-25 binds to both cAMP-GEFII and RIM2, and that this binding mediates the effects of cAMP on exocytosis.
The blind-drunk mouse carries a mutation in SNAP-25 that results in increased binding affinities within the SNARE-complex and the consequence in pancreatic β-cells are impaired vesicle recycling and granule exocytosis.
These results together demonstrate the significance of a functional exocytotic machinery for β-cells to respond satisfying to an elevation in blood glucose.
SNAP-25 and syntaxin 1 was discovered to be situated in clusters along the plasma membrane. Immunoneutralization of syntaxin 1 and SNAP-25 resulted in a strongly reduced exocytotic response of primed granules in close association with the voltage-dependent calcium channels.
Cholesterol is an essential component of the plasma membrane. Desorption of cholesterol from the plasma membrane in β-cells were accompanied with an overall reduction in the response of β-cells, from insulin secretion to exocytosis. We believe this is due to disturbance of a basic mechanism. Indeed, we found that SNAP-25 migrated from the plasma membrane out to the cytosol.
The stimulating effect of cAMP on insulin secretion is implemented through different pathways. One pathway is through cAMP-GEFII and its downstream affector RIM2. We show that SNAP-25 binds to both cAMP-GEFII and RIM2, and that this binding mediates the effects of cAMP on exocytosis.
The blind-drunk mouse carries a mutation in SNAP-25 that results in increased binding affinities within the SNARE-complex and the consequence in pancreatic β-cells are impaired vesicle recycling and granule exocytosis.
These results together demonstrate the significance of a functional exocytotic machinery for β-cells to respond satisfying to an elevation in blood glucose.
| Original language | English |
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| Qualification | Doctor |
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| Supervisors/Advisors |
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| Award date | 2008 Feb 29 |
| Publisher | |
| ISBN (Print) | 978-91-85897-66-7 |
| Publication status | Published - 2008 |
Bibliographical note
Defence detailsDate: 2008-02-29
Time: 09:15
Place: Lilla Aulan, Medicinskt Forskningscentrum, ingång 59, Universitetssjukhuset MAS,
External reviewer(s)
Name: Regazzi, Romano
Title: Associate Professor
Affiliation: Department of Cell Biology and Morphology, University of Lausanne, Swizerland
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Subject classification (UKÄ)
- Endocrinology and Diabetes
Free keywords
- calcium channel
- cAMP
- syntaxin 1
- SNAP-25
- SNARE
- exocytosis
- Insulin secretion
- pancreatic beta-cells
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Dive into the research topics of 'Exocytosis in insulin secreting cells - role of SNARE-proteins'. Together they form a unique fingerprint.Research output
- 2 Article
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A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse
Jeans, A. F., Oliver, P. L., Johnson, R., Capogna, M., Vikman, J., Molnar, Z., Babbs, A., Partridge, C. J., Salehi, A., Bengtsson, M., Eliasson, L., Rorsman, P. & Davies, K. E., 2007, In: Proceedings of the National Academy of Sciences. 104, 7, p. 2431-2436Research output: Contribution to journal › Article › peer-review
Open Access -
Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells.
Vikman, J., Ma, X., Hockerman, G. H., Rorsman, P. & Eliasson, L., 2006, In: Journal of Molecular Endocrinology. 36, 3, p. 503-515Research output: Contribution to journal › Article › peer-review