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A role for Sec1/Munc18 proteins in platelet exocytosis.

A critical aspect of haemostasis is the release of clot-forming components from the three intra-platelet stores: dense-core granules, alpha 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.

Pubmed ID: 12773094

Authors

  • Schraw TD
  • Lemons PP
  • Dean WL
  • Whiteheart SW

Journal

The Biochemical journal

Publication Data

August 15, 2003

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL56652

Mesh Terms

  • Amino Acid Sequence
  • Base Sequence
  • Blood Platelets
  • Cloning, Molecular
  • Cytoplasmic Granules
  • DNA Primers
  • DNA, Complementary
  • Escherichia coli
  • Exocytosis
  • Gene Library
  • Humans
  • Lysosomes
  • Membrane Proteins
  • Molecular Sequence Data
  • Munc18 Proteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Polymerase Chain Reaction
  • Recombinant Proteins
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Vesicle-Associated Membrane Protein 3
  • Vesicular Transport Proteins