title: Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members.
abstract: BACKGROUND
  TMEM16A and 16B work as Cl(-) channel, whereas 16F works as phospholipid scramblase. The function of other TMEM16 members is unknown.
  
  
  RESULTS
  Using TMEM16F(-/-) cells, TMEM16C, 16D, 16F, 16G, and 16J were shown to be lipid scramblases.
  
  
  CONCLUSIONS
  Some TMEM16 members are divided into two Cl(-) channels and five lipid scramblases.
  
  
  CONCLUSIONS
  Learning the biochemical function ofTMEM16family members is essential to understand their physiological role. Asymmetrical distribution of phospholipids between the inner and outer plasma membrane leaflets is disrupted in various biological processes. We recently identified TMEM16F, an eight-transmembrane protein, as a Ca(2+)-dependent phospholipid scramblase that exposes phosphatidylserine (PS) to the cell surface. In this study, we established a mouse lymphocyte cell line with a floxed allele in the TMEM16F gene. When TMEM16F was deleted, these cells failed to expose PS in response to Ca(2+) ionophore, but PS exposure was elicited by Fas ligand treatment. We expressed other TMEM16 proteins in the TMEM16F(-/-) cells and found that not only TMEM16F, but also 16C, 16D, 16G, and 16J work as lipid scramblases with different preference to lipid substrates. On the other hand, a patch clamp analysis in 293T cells indicated that TMEM16A and 16B, but not other family members, acted as Ca(2+)-dependent Cl(-) channels. These results indicated that among 10 TMEM16 family members, 7 members could be divided into two subfamilies, Ca(2+)-dependent Cl(-) channels (16A and 16B) and Ca(2+)-dependent lipid scramblases (16C, 16D, 16F, 16G, and 16J).
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imao
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuba
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000075368:Anoctamins; D017209:Apoptosis; D000001:Calcimycin / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D020013:Calcium Signaling; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D058977:Molecular Sequence Annotation; D009928:Organ Specificity; D010718:Phosphatidylserines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C576687:ANO6 protein, mouse; D000075368:Anoctamins; D061207:Calcium Ionophores; C491899:Fas protein, mouse; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D019014:fas Receptor; D000001:Calcimycin
keywords: Calcium; Cl- Channel; Lipid Transport; Phosphatidylcholine; Phosphatidylserine; Phospholipid Scramblase; Plasma Membrane; TMEM16; Tissue-specific Expression