Lipid asymmetry and membrane trafficking: Transbilayer distribution of structural phospholipids as regulators of exocytosis and endocytosis

The plasma membrane of eukaryotic cells is highly dynamic and asymmetrically organized. Its continuous remodeling plays a crucial role in diverse cellular processes, including apoptosis, blood coagulation, and vesicular trafficking. The distribution and rearrangement of phospholipids (PLs) within the bilayer are tightly regulated, influencing membrane curvature, tension, and organization. This review examines the role of PL asymmetry in vesicle fusion, the final step of exocytosis, and in vesicular membrane retrieval by compensatory endocytosis in neurosecretory cells, with a particular emphasis on structural PLs such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). We discuss the molecular mechanisms that maintain and disrupt PLs asymmetry and explore how lipid rearrangements affect vesicle dynamics. Additionally, we highlight recent findings on lipid scramblases, particularly phospholipid scramblase-1 (PLSCR1), and their role in regulated exocytosis and compensatory endocytosis.