title: TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets.
abstract: Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca(2+) ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca(2+)-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.
authors.affiliation: Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan;
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan;
authors.forename: Asuka
authors.initials: A
authors.lastname: Sakata
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan; Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.affiliation: Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan; snagata@ifrec.osaka-u.ac.jp.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000075368:Anoctamins; D001777:Blood Coagulation / Q000235:genetics; D001778:Blood Coagulation Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010718:Phosphatidylserines / Q000235:genetics / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D015539:Platelet Activation; D013917:Thrombin / Q000235:genetics / Q000378:metabolism
chemical_list: C576687:ANO6 protein, mouse; C555078:ANO6 protein, human; D000075368:Anoctamins; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D013917:Thrombin; D002118:Calcium
keywords: calcium; microvesicles; phosphatidylserine; platelets; scramblase