Scientists at Kyoto University’s Institute for Integrated Cellular Materials Science (WPI-iCeMS) have uncovered new details about how cells manage the distribution of lipids in their cell membrane. These lipids, known as phospholipids, are arranged in a membrane bilayer, regulating the entry and exit of certain molecules to maintain a stable internal environment.
Phospholipids are typically unevenly distributed across the cell membrane, with some types remaining on the inside and others on the outside. However, cells need to change this distribution quickly in response to environmental or internal cues. The process of moving phospholipids from one side of the membrane to the other, known as phospholipid shuffling, can expose specific phospholipids to the outside of the cell. This exposure is important for several functions, including blood clotting and the removal of unwanted cells.
The new research, published in Nature CommunicationsThey identified protein complexes that play an essential role in this process. “We found that when calcium enters cells, a specific protein complex, including the ion channel Tmem63b and the vitamin B1 transporter Slc19a2, triggers the alteration of phospholipids,” explains Professor Jun Suzuki, who led the study.
Calcium acts as a signal that can trigger several cellular processes, such as ion channel activation and phospholipid coding when it enters the cell. “When Tmem63b was deleted, cells lost calcium-induced phospholipid coding activity,” says Han Niu, the first author of the study. “In contrast, certain genetic mutations in the Tmem63b gene linked to diseases such as epilepsy and anemia lead to continued activation of phospholipid coding, even without calcium stimulation.”
The researchers also found that Kcnn4, a calcium-activated potassium channel, influences this process. When either Slc19a2 or Kcnn4 was missing, phospholipid coding was decreased. This demonstrates that Tmem63b, Slc19a2, and Kcnn4 work together to regulate phospholipid coding.
Previous studies by Suzuki and his colleagues had identified other proteins involved in phospholipid alteration, but they were unable to explain all cases. The new discovery shows that Tmem63b and Slc19a2 work together as a bound pair to trigger this process, while the other proteins function as pairs formed by two copies of the same protein.
The team also found that changes in the cell’s plasma membrane tension could help activate the Tmem63b/Slc19a2 complex. When calcium enters the cell and potassium ions exit via Kcnn4, it can cause the cell to shrink. This contraction can lead to changes in cell membrane tension, facilitating activation of Tmem63b with an increase in intracellular calcium. This activation mechanism could explain how neuronal cells and red blood cells adapt to environmental changes through phospholipid coding.
The researchers hope their findings will lead to new treatments for diseases in which phospholipid coding is disrupted, including epilepsy and anemia.