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

Cell | Sep 28, 2012

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 RIS Download

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

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Associated grants

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

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