Dr. Sugasawa’s Research

Structural basis of lipid and anesthetic action on TMEM16 scramblases

The TMEM16 family of membrane proteins are Ca2+-dependent phospholipid scramblases. A critical function of TMEM16 scramblases is the externalization of phosphatidylserine (PS), which predominately resides in the inner leaflet of the plasma membrane. Exposure of PS is essential for platelet-mediated activation of blood coagulation as well as regulation of apoptosis and inflammatory responses. We show that the TMEM16 scramblase, nhTMEM16, is inhibited by cholesterol in a liposome scramblase assay. Also, recent studies have shown that TMEM16 scramblases are modulated by various lipids such as long-chain phospholipids and ceramides. Thus, lipid modulators offer a potential avenue to modulate TMEM16 scramblase activity and physiologic processes such as coagulation and neuroapoptosis, which are particularly relevant in the perioperative period. The molecular mechanisms by which TMEM16 scramblases are modulated by lipids are not understood, and whether other hydrophobic molecules such as anesthetics modulate TMEM16 scramblases is unknown. The overarching goal of this project is to characterize the pharmacology of lipid and anesthetic modulation of nhTMEM16, and determine the stoichiometry and sites of binding that mediate the modulatory effects. Since anesthetics also affect blood coagulation, apoptosis and inflammatory responses resulting in adverse clinical outcomes, we will test the hypothesis that TMEM16 scramblases are modulated by anesthetics. The outcome of this project will provide novel information on the sites of small molecule modulation of TMEM16 scramblases, which may facilitate structure-based design of TMEM16 modulators.