title: Syntaxin 8 regulates platelet dense granule secretion, aggregation, and thrombus stability.
abstract: Platelet secretion not only drives thrombosis and hemostasis, but also mediates a variety of other physiological and pathological processes. The ubiquitous SNARE machinery and a number of accessory proteins have been implicated in regulating secretion in platelet. Although several platelet SNAREs have been identified, further members of the SNARE family may be needed to fine-tune platelet secretion. In this study we identified expression of the t-SNARE syntaxin 8 (STX8) (Qc SNARE) in mouse and human platelets. In mouse studies, whereas STX8 was not essential for α-granule or lysosome secretion, Stx8(-/-) platelets showed a significant defect in dense granule secretion in response to thrombin and CRP. This was most pronounced at intermediate concentrations of agonists. They also showed an aggregation defect that could be rescued with exogenous ADP and increased embolization in Stx8(-/-) mice in vivo consistent with an important autocrine and paracrine role for ADP in aggregation and thrombus stabilization. STX8 therefore specifically contributes to dense granule secretion and represents another member of a growing family of genes that play distinct roles in regulating granule release from platelets and thus platelet function in thrombosis and hemostasis.
authors.affiliation: From the School of Physiology and Pharmacology, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom.
authors.forename: Ewelina M
authors.initials: EM
authors.lastname: Golebiewska
authors.affiliation: From the School of Physiology and Pharmacology, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harper
authors.affiliation: From the School of Physiology and Pharmacology, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Williams
authors.affiliation: the School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Savage
authors.affiliation: the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Goggs
authors.affiliation: the Fakultät für Chemie, Biochemie III, Universität Bielefeld, Postfach 100131, 33501 Bielefeld, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fischer von Mollard
authors.affiliation: From the School of Physiology and Pharmacology, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom, a.poole@bris.ac.uk.
authors.forename: Alastair W
authors.initials: AW
authors.lastname: Poole
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004072:Digitonin / Q000737:chemistry; D005089:Exocytosis; D005434:Flow Cytometry; D006487:Hemostasis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015539:Platelet Activation; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000502:physiology*; D050600:SNARE Proteins / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
chemical_list: D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D004072:Digitonin
keywords: ADP; Exocytosis; Platelet; SNARE Proteins; Thrombosis