Scientists have revealed fresh insights into how cells control the distribution of lipids in their membranes. These lipids, referred to as phospholipids, are organized in a bilayer configuration that manages the passage of specific molecules, ensuring a stable internal environment.
Researchers at Kyoto University’s Institute for Integrated Cell-Material Sciences (WPI-iCeMS) have revealed fresh insights into how cells control the distribution of lipids in their membranes. These lipids, referred to as phospholipids, are organized in a bilayer configuration that manages the passage of specific molecules, ensuring a stable internal environment.
Phospholipids are typically distributed unevenly within the cell membrane, with certain types residing on the inner layer and others on the outer layer. However, cells need to rapidly alter this distribution in reaction to environmental or internal signals. The technique of relocating phospholipids from one side of the membrane to the other, known as phospholipid scrambling, allows specific phospholipids to become exposed on the cell’s exterior. This exposure plays a crucial role in several biological functions, including blood clotting and the elimination of unwanted cells.
The recent study, published in Nature Communications, identified key protein complexes that are vital to this process. “We found that when calcium enters the cell, a specific protein complex—which includes the ion channel Tmem63b and the vitamin B1 transporter Slc19a2—initiates phospholipid scrambling,” says Professor Jun Suzuki, who led the study.
Calcium acts as a signaling molecule that can trigger various cellular activities, such as ion channel gating and phospholipid scrambling upon entering the cell. “When Tmem63b was removed, the cells lost their ability to scramble phospholipids in response to calcium,” notes Han Niu, the study’s primary author. “On the other hand, specific genetic mutations in the Tmem63b gene associated with conditions like epilepsy and anemia result in ongoing phospholipid scrambling, even without calcium presence.”
The researchers also discovered that Kcnn4, a potassium channel activated by calcium, plays a role in this mechanism. In the absence of either Slc19a2 or Kcnn4, phospholipid scrambling was diminished. This demonstrates that Tmem63b, Slc19a2, and Kcnn4 collaborate to manage phospholipid scrambling.
Previous research by Suzuki and his team had pinpointed other proteins involved in phospholipid scrambling, but these were not able to clarify all scenarios. The recent findings illustrate that Tmem63b and Slc19a2 function as a duo working together to trigger the process, while other proteins operate in pairs composed of two identical proteins.
The team also discovered that alterations in the tension of the cell’s plasma membrane may assist in activating the Tmem63b/Slc19a2 complex. When calcium flows into the cell and potassium ions exit via Kcnn4, this can lead to cell shrinkage. Such shrinkage may modify the tension of the cell membrane, which could activate Tmem63b as intracellular calcium levels rise. This activation process might explain how neuronal cells and red blood cells adjust to environmental changes through phospholipid scrambling.
The researchers are hopeful that these discoveries could pave the way for new therapies for diseases where phospholipid scrambling is impacted, such as epilepsy and anemia.
