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 Ca2+-activated Cl- channels (CaCCs) is linked to Scott Syndrome with deficient Ca2+-dependent lipid scrambling. We generated TMEM16F-knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca2+-dependent phosphatidylserine exposure and procoagulant activity, and lack a Ca2+-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a novel Small-conductance Ca2+-Activated Non-selective cation (SCAN) current with sub-picosiemens single channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations including Ca2+, and exhibit synergistic gating by Ca2+ 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 novel Ca2+-activated channel permeable to Ca2+ and critical for Ca2+-dependent scramblase activity.