New proteins involved in regulating the cell membrane

Scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (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 bilayer of membranes, regulating entry and exit of certain molecules to maintain a stable internal environment.

Phospholipids are usually distributed unevenly across the cell membrane, with some types staying on the inside and others on the outer side. However, cells need to change this distribution quickly in response to environmental or internal signals. The process of moving phospholipids from one side of the membrane to the other, known as phospholipid scrambling, 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 Communications, identified protein complexes that play an essential role in this process. “We discovered 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,” explains Professor Jun Suzuki, who led the study.

Calcium serves as a signal that can activate various cellular processes such as ion channel gating and phospholipid scrambling when it enters the cell. “When Tmem63b was deleted, the cells lost calcium-induced phospholipid scrambling activity” says Han Niu, the study’s first author. “Conversely, certain genetic mutations in the Tmem63b gene linked to diseases like epilepsy and anemia lead to continuous activation of phospholipid scrambling, even without calcium stimulation.”

The researchers also found that Kcnn4, a potassium channel activated by calcium, influences this process. When either Slc19a2 or Kcnn4 was missing, phospholipid scrambling decreased. This shows that Tmem63b, Slc19a2, and Kcnn4 work together to regulate phospholipid scrambling.

Earlier studies by Suzuki and colleagues had identified other proteins involved in phospholipid scrambling, but they couldn’t explain all cases. The new discovery shows that Tmem63b and Slc19a2 work together as a pair bound together to trigger this process, whereas the other proteins work as pairs made of two copies of the same protein.

The team also found that changes in the tension of the cell's plasma membrane might help activate the Tmem63b/Slc19a2 complex. When calcium enters the cell and potassium ions leave by Kcnn4, it can cause the cell to shrink. This shrinkage can cause changes in the cell membrane tension, facilitating activation of Tmem63b with 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 lead to new treatments for diseases in which phospholipid scrambling is disrupted, including epilepsy and anemia.

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Paper:
“Phospholipid scrambling induced by an ion channel/metabolite transporter complex”
Nature Communications 15, 7566｜DOI: https://doi.org/10.1038/s41467-024-51939-w

About Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS):
At iCeMS, our mission is to explore the secrets of life by creating compounds to control cells, and further down the road to create life-inspired materials.
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For more information, contact:
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