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Exocytosis in insulin secreting cells - role of SNARE-proteins

Vikman, Jenny LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:13.
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.... (More)
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. (Less)
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author
supervisor
opponent
  • Associate Professor Regazzi, Romano, Department of Cell Biology and Morphology, University of Lausanne, Swizerland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
calcium channel, cAMP, syntaxin 1, SNAP-25, SNARE, exocytosis, Insulin secretion, pancreatic beta-cells
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:13
pages
114 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Lilla Aulan, Medicinskt Forskningscentrum, ingång 59, Universitetssjukhuset MAS,
defense date
2008-02-29 09:15
ISSN
1652-8220
ISBN
978-91-85897-66-7
language
English
LU publication?
yes
id
470cb063-6c13-4dab-8e31-cc5b22231a04 (old id 1021812)
date added to LUP
2008-02-04 11:17:27
date last changed
2016-09-19 08:44:45
@phdthesis{470cb063-6c13-4dab-8e31-cc5b22231a04,
  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.<br/><br>
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.<br/><br>
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.<br/><br>
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.<br/><br>
 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.<br/><br>
These results together demonstrate the significance of a functional exocytotic machinery for β-cells to respond satisfying to an elevation in blood glucose.},
  author       = {Vikman, Jenny},
  isbn         = {978-91-85897-66-7},
  issn         = {1652-8220},
  keyword      = {calcium channel,cAMP,syntaxin 1,SNAP-25,SNARE,exocytosis,Insulin secretion,pancreatic beta-cells},
  language     = {eng},
  pages        = {114},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Exocytosis in insulin secreting cells - role of SNARE-proteins},
  volume       = {2008:13},
  year         = {2008},
}