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Vol. 18, Issue 1, 24-33, January 2007
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*Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536; and Membrane Biology Laboratory, Institute of Molecular and Cellular Biology, Proteos, Singapore 138673, Singapore
Submitted September 5, 2006;
Revised October 5, 2006;
Accepted October 16, 2006
Monitoring Editor: Sean Munro
Platelet secretion is critical to hemostasis. Release of granular cargo is mediated by soluble NSF attachment protein receptors (SNAREs), but despite consensus on t-SNAREs usage, it is unclear which Vesicle Associated Membrane Protein (VAMPs: synaptobrevin/VAMP-2, cellubrevin/VAMP-3, TI-VAMP/VAMP-7, and endobrevin/VAMP-8) is required. We demonstrate that VAMP-8 is required for release from dense core granules, alpha granules, and lysosomes. Platelets from VAMP-8–/– mice have a significant defect in agonist-induced secretion, though signaling, morphology, and cargo levels appear normal. In contrast, VAMP-2+/–, VAMP-3–/–, and VAMP-2+/–/VAMP-3–/– platelets showed no defect. Consistently, tetanus toxin had no effect on secretion from permeabilized mouse VAMP-3–/– platelets or human platelets, despite cleavage of VAMP-2 and/or -3. Tetanus toxin does block the residual release from permeabilized VAMP-8–/– platelets, suggesting a secondary role for VAMP-2 and/or -3. These data imply a ranked redundancy of v-SNARE usage in platelets and suggest that VAMP-8–/– mice will be a useful in vivo model to study platelet exocytosis in hemostasis and vascular inflammation.
The online version of this contains supplemental material at MBC Online (http://www.molbiolcell.org). This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-09-0785 on October 25, 2006.
Address correspondence to: Sidney W. Whiteheart (whitehe{at}uky.edu)
Abbreviations used: VAMP, vesicle associate membrane protein; TeNT LC, tetanus toxin light chain; TI-VAMP, tetanus toxin insensitive VAMP; WT, wild type; RT, room temperature (
25°C); PF4, platelet factor IV; OCS, open canalicular system; 5-HT, 5 hydroxy-tryptophan (serotonin); SLO, streptolysin O; PRP, platelet-rich plasma; DC, dense core.
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