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

Published

Journal Article

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:

Full Text

Duke Authors

Cited Authors

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

Published Date

  • September 28, 2012

Published In

Volume / Issue

  • 151 / 1

Start / End Page

  • 111 - 122

PubMed ID

  • 23021219

Pubmed Central ID

  • 23021219

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.07.036

Language

  • eng

Conference Location

  • United States