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TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation.


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:

Pubmed ID: 23021219


  • Yang H
  • Kim A
  • David T
  • Palmer D
  • Jin T
  • Tien J
  • Huang F
  • Cheng T
  • Coughlin SR
  • Jan YN
  • Jan LY



Publication Data

September 28, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL65185
  • Agency: NIMH NIH HHS, Id: MH65334
  • Agency: NHLBI NIH HHS, Id: R01 HL065185
  • Agency: NINDS NIH HHS, Id: R01 NS069229
  • Agency: NIMH NIH HHS, Id: R37 MH065334

Mesh Terms

  • Ambystoma mexicanum
  • Animals
  • Blood Coagulation
  • Blood Platelets
  • Calcium
  • Chloride Channels
  • Hemostasis
  • Lipid Metabolism
  • Megakaryocytes
  • Mice
  • Mice, Knockout
  • Oocytes
  • Phospholipid Transfer Proteins
  • Xenopus