title: TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation.
abstract: Collapse of membrane lipid asymmetry is a hallmark of blood coagulation. TMEM16F of the TMEM16 family that includes TMEM16A/B Ca(2+)-activated Cl(-) channels (CaCCs) is linked to Scott syndrome with deficient Ca(2+)-dependent lipid scrambling. We generated TMEM16F knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca(2+)-dependent phosphatidylserine exposure and procoagulant activity and lack a Ca(2+)-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a small-conductance Ca(2+)-activated nonselective cation (SCAN) current with subpicosiemens single-channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations, including Ca(2+), and exhibit synergistic gating by Ca(2+) and voltage. We further pinpointed a residue in the putative pore region important for the cation versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels. This study thus identifies a Ca(2+)-activated channel permeable to Ca(2+) and critical for Ca(2+)-dependent scramblase activity during blood coagulation. PAPERFLICK:
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, 94143, USA.
authors.forename: Huanghe
authors.initials: H
authors.lastname: Yang
authors.forename: Andrew
authors.initials: A
authors.lastname: Kim
authors.forename: Tovo
authors.initials: T
authors.lastname: David
authors.forename: Daniel
authors.initials: D
authors.lastname: Palmer
authors.forename: Taihao
authors.initials: T
authors.lastname: Jin
authors.forename: Jason
authors.initials: J
authors.lastname: Tien
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.forename: Tong
authors.initials: T
authors.lastname: Cheng
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
mesh_terms: D000558:Ambystoma mexicanum; D000818:Animals; D000075369:Anoctamin-1; D000075368:Anoctamins; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000378:metabolism; D006487:Hemostasis; D050356:Lipid Metabolism; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: C531181:ANO1 protein, mouse; C576687:ANO6 protein, mouse; D000075369:Anoctamin-1; D000075368:Anoctamins; D018118:Chloride Channels; D049294:Phospholipid Transfer Proteins; D002118:Calcium