A critical aspect of haemostasis is the release of clot-forming components from the three intra-platelet stores: dense-core granules, α granules and lysosomes. Exocytosis from these granules is mediated by soluble proteins [N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAPs)] and integral membrane proteins [vesicle and target SNAP receptors (v- and t-SNAREs)]. Three Sec1/Munc18 proteins (SM proteins) are present in platelets (Munc18a, Munc18b and Munc18c) and they bind to and potentially regulate specific syntaxin t-SNAREs. In resting platelets, these SM proteins associate with granules and open canalicular system membranes predominantly but not with the plasma membrane. Munc18a binds to syntaxin 2 alone and does not associate with other members of the core SNARE complex. Munc18b associates with a larger complex that contains synaptosome-associated protein of 23 kDa (SNAP-23) and cellubrevin/vesicle-associated membrane protein 3. Munc18c associates with both syntaxins 2 and 4, with synaptosome-associated protein of 23 kDa (SNAP-23) and with a v-SNARE. On stimulation, most of the platelet SM proteins are still found in membrane fractions. Phosphorylation of each Munc18 increases in thrombin-treated cells and phosphorylated Munc18c remains associated with syntaxins 2 and 4, but its affinity for the SNAREs appears to be reduced. To determine the functional role of the platelet SM proteins, we examined the effects of Munc18-based peptides (Munc18a peptide 3 and Munc18c peptide 3). Addition of the peptides to permeabilized platelets inhibits secretion from all three platelet granules. These peptides also inhibit agonist-induced aggregation in saponin-permeabilized platelets. These studies demonstrate a clear role for SM proteins in platelet exocytosis and aggregation and suggest a dominant role for Munc18c in all three granule-release events.
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August 2003
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Research Article|
August 15 2003
A role for Sec1/Munc18 proteins in platelet exocytosis
Todd D. SCHRAW;
Todd D. SCHRAW
∗Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 800 Rose Street, Lexington, KY 40536, U.S.A.
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Paula P. LEMONS;
Paula P. LEMONS
∗Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 800 Rose Street, Lexington, KY 40536, U.S.A.
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William L. DEAN;
William L. DEAN
†Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292, U.S.A.
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Sidney W. WHITEHEART
Sidney W. WHITEHEART
1
∗Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 800 Rose Street, Lexington, KY 40536, U.S.A.
1To whom correspondence should be addressed (e-mail whitehe@pop.uky.edu).
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Publisher: Portland Press Ltd
Received:
April 23 2003
Revision Received:
May 27 2003
Accepted:
May 29 2003
Accepted Manuscript online:
May 29 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 374 (1): 207–217.
Article history
Received:
April 23 2003
Revision Received:
May 27 2003
Accepted:
May 29 2003
Accepted Manuscript online:
May 29 2003
Citation
Todd D. SCHRAW, Paula P. LEMONS, William L. DEAN, Sidney W. WHITEHEART; A role for Sec1/Munc18 proteins in platelet exocytosis. Biochem J 15 August 2003; 374 (1): 207–217. doi: https://doi.org/10.1042/bj20030610
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