Scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences have discovered new insights into how cells manage the distribution of lipids in their cell membrane. Phospholipids, which regulate the entry and exit of molecules to maintain a stable internal environment, are usually unevenly distributed across the membrane. Cells must change this distribution quickly in response to various signals, a process known as phospholipid scrambling. This scrambling can expose specific phospholipids to the outside of the cell, aiding in functions like blood clotting and removing unwanted cells.
In a study published in Nature Communications, researchers identified protein complexes involved in phospholipid scrambling. The team found that when calcium is incorporated into cells, a specific protein complex including the ion channel Tmem63b and the vitamin B1 transporter Slc19a2 triggers phospholipid scrambling. Calcium acts as a signal that can activate cellular processes, such as ion channel gating and phospholipid scrambling, when it enters the cell. When Tmem63b was deleted, cells lost calcium-induced phospholipid scrambling activity, while mutations in the Tmem63b gene linked to diseases like epilepsy and anemia led to continuous activation of phospholipid scrambling.
The researchers also discovered that Kcnn4, a potassium channel activated by calcium, influences phospholipid scrambling. When either Slc19a2 or Kcnn4 was missing, phospholipid scrambling decreased, indicating that Tmem63b, Slc19a2, and Kcnn4 work together to regulate this process. Previous studies had identified other proteins involved in phospholipid scrambling, but the discovery of Tmem63b and Slc19a2 working in pairs sheds new light on this mechanism.
Changes in the tension of the cell’s plasma membrane may also play a role in activating the Tmem63b/Slc19a2 complex. When calcium enters the cell and potassium ions leave via Kcnn4, the cell can shrink, leading to changes in membrane tension that facilitate Tmem63b activation with an increase in intracellular calcium. This activation mechanism could explain how neuronal cells and red blood cells adapt to environmental changes through phospholipid scrambling.
The researchers hope that their findings will pave the way for new treatments for diseases where phospholipid scrambling is disrupted, such as epilepsy and anemia. Understanding the molecular mechanisms behind phospholipid scrambling could offer insights into developing targeted therapies that restore normal lipid distribution in cell membranes. Further research into the role of these protein complexes in various cellular functions could expand our knowledge of cell membrane dynamics and potentially lead to novel therapeutic strategies.
