The complementary roles of VAMP-2, -3, and -7 in platelet secretion and function
Creators: name: Joshi, Smita
name: Prakhya, Kanakanagavalli Shravani
name: Smith, Alexis N.
name: Chanzu, Harry
name: Zhang, Ming
name: Whiteheart, Sidney W.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Sociology
subject: FOS: Sociology
subject: Biological Sciences not elsewhere classified
subject: Science Policy
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences

description: Platelet secretion requires Soluble N-ethylmaleimide Sensitive Attachment Protein Receptors (SNAREs). Vesicle SNAREs/Vesicle-Associated Membrane Proteins (v-SNAREs/VAMPs) on granules and t-SNAREs in plasma membranes mediate granule release. Platelet VAMP heterogeneity has complicated the assessment of how/if each is used and affects hemostasis. To address the importance of VAMP-7 (V7), we analyzed mice with global deletions of V3 and V7 together or platelet-specific deletions of V2, V3, and global deletion of V7. We measured the kinetics of cargo release, and its effects on three injury models to define the context-specific roles of these VAMPs. Loss of V7 minimally affected dense and α granule release but did affect lysosomal release. V3<sup>−/−</sup>7<sup>−/−</sup> and V2<sup>Δ</sup>3<sup>Δ</sup>7<sup>−/−</sup> platelets showed partial defects in α and lysosomal release; dense granule secretion was unaffected. <i>In vivo</i> assays showed that loss of V2, V3, and V7 caused no bleeding or occlusive thrombosis. These data indicate a role for V7 in lysosome release that is partially compensated by V3. V7 and V3, together, contribute to α granule release, however none of these deletions affected hemostasis/thrombosis. Our results confirm the dominance of V8. When it is present, deletion of V2, V3, or V7 alone or in combination minimally affects platelet secretion and hemostasis. <b>What did we know?</b>V8 is the primary VAMP isoform for platelet granule secretion, but V2 and V3 play compensatory roles.V3 is important for platelet endocytosis.V7 plays a minimal role in secretion and does not affect hemostasis. V8 is the primary VAMP isoform for platelet granule secretion, but V2 and V3 play compensatory roles. V3 is important for platelet endocytosis. V7 plays a minimal role in secretion and does not affect hemostasis. <b>What did we discover?</b>The loss of both V3 and V7 increases α and lysosomal secretion defects.Platelet-specific deletion of V2 and V3 with global V7-deletion causes defective α and lysosomal release.Secretion deficiencies in V3<sup>−/−</sup>7<sup>−/−</sup> and V2<sup>Δ</sup>3<sup>Δ</sup>7<sup>−/−</sup> have no effect on hemostasis or thrombosis. The loss of both V3 and V7 increases α and lysosomal secretion defects. Platelet-specific deletion of V2 and V3 with global V7-deletion causes defective α and lysosomal release. Secretion deficiencies in V3<sup>−/−</sup>7<sup>−/−</sup> and V2<sup>Δ</sup>3<sup>Δ</sup>7<sup>−/−</sup> have no effect on hemostasis or thrombosis. <b>What is the impact?</b>We show that endosomal v-SNAREs (V3 and V7) play minor roles in secretion.V3<sup>−/−</sup>7<sup>−/−</sup> and platelet-specific V2<sup>Δ</sup>3<sup>Δ</sup>7<sup>−/−</sup> mice are viable and will be valuable in <i>in vivo</i> studies of membrane trafficking. We show that endosomal v-SNAREs (V3 and V7) play minor roles in secretion. V3<sup>−/−</sup>7<sup>−/−</sup> and platelet-specific V2<sup>Δ</sup>3<sup>Δ</sup>7<sup>−/−</sup> mice are viable and will be valuable in <i>in vivo</i> studies of membrane trafficking.