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Vol. 18, Issue 1, 24-33, January 2007

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Endobrevin/VAMP-8 Is the Primary v-SNARE for the Platelet Release Reaction

Qiansheng Ren^*, Holly Kalani Barber^*, Garland L. Crawford^*, Zubair A. Karim^*, Chunxia Zhao^*, Wangsun Choi^*, Cheng-Chun Wang, Wanjin Hong, and Sidney W. Whiteheart^*

*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.

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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