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Query: UMLS:C0344329 (
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28,634
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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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:
...
PMID:TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. 2302 Dec 19
TMEM16F
, which is activated by elevation of intracellular calcium to trigger phospholipid scrambling and the
collapse
of lipid bilayer asymmetry to mediate important cellular functions such as blood coagulation, also generates a small-conductance calcium-activated cation current. How
TMEM16F
activation may be regulated is an open question. By recording
TMEM16F
Ca
2+
-activated current, we found that the
TMEM16F
Ca
2+
-response is desensitized by a brief exposure to high intracellular Ca
2+
, which is associated with depletion of phosphatidylinositol-(4, 5)-bisphosphate (PIP
2
) from the inner leaflet of the membrane. Application of artificial or natural PIP
2
restores
TMEM16F
channel activity. PIP
2
modulation of
TMEM16F
requires the presence of several positively charged amino acids in its cytoplasmic N-terminal domain.
TMEM16F
interaction with PIP
2
works synergistically with membrane depolarization to facilitate Ca
2+
-gating of
TMEM16F
. Our study reveals the dependence of
TMEM16F
activity on phosphoinositides and provides one mechanism for
TMEM16F
activation to be strictly regulated in the cell membrane.
...
PMID:Phosphatidylinositol-(4, 5)-bisphosphate regulates calcium gating of small-conductance cation channel TMEM16F. 2938 63
Calcium-activated phospholipid scramblase mediates the energy-independent bidirectional translocation of lipids across the bilayer, leading to transient or, in the case of apoptotic scrambling, sustained
collapse
of membrane asymmetry. Cells lacking
TMEM16F
-dependent lipid scrambling activity are deficient in generation of extracellular vesicles (EVs) that shed from the plasma membrane in a Ca
2+
-dependent manner, namely microvesicles. We have adapted chemical induction of giant plasma membrane vesicles (GPMVs), which require both
TMEM16F
-dependent phospholipid scrambling and calcium influx, as a kinetic assay to investigate the mechanism of
TMEM16F
activity. Using the GPMV assay, we identify and characterize both inactivating and activating mutants that elucidate the mechanism for
TMEM16F
activation and facilitate further investigation of
TMEM16F
-mediated lipid translocation and its role in extracellular vesiculation.
...
PMID:Chemically induced vesiculation as a platform for studying TMEM16F activity. 3062 79
