TMEM16F Ion Channel Regulates Calcium-Dependent PS Exposure, Hemostasis, and Thrombosis

Abstract 1111

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 associated with platelet deficiency in Ca²⁺-dependent phosphatidylserine exposure and procoagulant activity, and lack a Ca²⁺-activated cation current in the platelet precursor megakaryocytes. TMEM16F 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.