Advancing mechanistic understanding of membrane ion and lipid transport

SUMMARY Dynamic trans-bilayer movement of ions and phospholipids across cell membranes is vital for cellular life and death. In stark contrast to our extensive understanding of membrane ion transport, the mechanisms and consequences of phospholipid flip-flop remain elusive. The TMEM16 transmembrane protein family, implicated in various diseases, such as heart attack, stroke, epilepsy, muscular dystrophy, cancer, and infections like AIDS and COVID-19, comprises both ion channels and lipid scramblases. By closely examining TMEM16 family members, our previous work has eliminated the conceptual barrier between ion channels and lipid scramblases, the two major types of passive transporters on cell membranes cooperating distinct substrates. This conceptual breakthrough has allowed us to determine novel ion and lipid transport principles at the molecular level and uncover new cellular and physiological functions for TMEM16 ion channels and lipid scramblases. In this application, we will investigate TMEM16 lipid scramblases to deepen our understanding of lipid flip-flop and its undiscovered cell signaling roles. We aim to develop innovative methods for monitoring and controlling lipid flip-flop under physiological conditions and to decipher how calcium and voltage activate TMEM16 lipid scramblases at molecular and cellular levels. Additionally, we will employ our novel methods to explore lipid scramblase-mediated cell signaling during cell-cell fusion, an essential yet poorly understood process for human health. Our proposed studies will offer a comprehensive understanding of lipid and ion transport in health and disease, paving the way for developing new therapies to prevent and treat a wide array of diseases, including stroke, heart attack, atherosclerosis, neurological disorders, infectious diseases, and pregnancy complications.