title: Dynamin-related protein-1 controls fusion pore dynamics during platelet granule exocytosis.
abstract: OBJECTIVE
  Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently expands to enable the extrusion of granule contents. However, the molecular mechanisms that control platelet fusion pore expansion and collapse are not known.
  
  
  RESULTS
  We identified dynamin-related protein-1 (Drp1) in platelets and found that an inhibitor of Drp1, mdivi-1, blocked exocytosis of both platelet dense and α-granules. We used single-cell amperometry to monitor serotonin release from individual dense granules and, thereby, measured the effect of Drp1 inhibition on fusion pore dynamics. Inhibition of Drp1 increased spike width and decreased prespike foot events, indicating that Drp1 influences fusion pore formation and expansion. Platelet-mediated thrombus formation in vivo after laser-induced injury of mouse cremaster arterioles was impaired after infusion of mdivi-1.
  
  
  CONCLUSIONS
  These results demonstrate that inhibition of Drp1 disrupts platelet fusion pore dynamics and indicate that Drp1 can be targeted to control thrombus formation in vivo.
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Secil
authors.initials: S
authors.lastname: Koseoglu
authors.forename: James R
authors.initials: JR
authors.lastname: Dilks
authors.forename: Christian G
authors.initials: CG
authors.lastname: Peters
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fitch-Tewfik
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Fadel
authors.forename: Reema
authors.initials: R
authors.lastname: Jasuja
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.forename: Christy L
authors.initials: CL
authors.lastname: Haynes
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft
mesh_terms: D000818:Animals; D001160:Arterioles / Q000293:injuries; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000097:blood*; D005089:Exocytosis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000097:blood*; D006801:Humans; D007834:Lasers; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D019007:P-Selectin / Q000097:blood; D052999:Quinazolinones / Q000494:pharmacology; D011817:Rabbits; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000097:blood; D013927:Thrombosis / Q000097:blood* / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D057772:Vascular System Injuries / Q000097:blood* / Q000209:etiology
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D005343:Fibrinolytic Agents; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D019007:P-Selectin; D052999:Quinazolinones; C546937:SELP protein, human; D012701:Serotonin; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins