EN / DA
Body and mind

Flippases give cells an electric shock

New research shows that phospholipid flippases create an electric current as these proteins move molecules of fat in the cell membrane. These flippases strongly influence the development of certain diseases.

Fifteen years ago, researchers did not know much about flippases, which are proteins that move (flip) certain molecules of fat from the outer to the inner layer of cell membranes.

Today, researchers know that flippases play a major role in the development of certain diseases. Further, new Danish research shows that when phospholipid flippases move the fat molecules in a cell membrane, they create electrical current.

Cells use electrical energy to control many functions, which is why this discovery makes flippases even more important for keeping people healthy.

“This basic research shows that some membrane proteins that were of little interest to us until a few years ago create an electrical current in the cells and thus probably play a role in many other cellular mechanisms,” explains a researcher behind the study, Jens Peter Andersen, Professor, Department of Biomedicine, Aarhus University.

The new study was published recently in Proceedings of the National Academy of Sciences of the United States of America.

Flippases move lipids in cell membranes

What are flippases?

Flippases are proteins present in cell membranes that move the fat molecules (lipids) that comprise the membranes of the cells.

Cell membranes have a bilayer of lipids: one layer faces the interior of the cell and the other faces externally.

The lipids differ in properties, and the phospholipid flippases studied by Jens Peter Andersen’s research group move the lipids called phosphatidylserine. More specifically, these flippases move phosphatidylserine from the outer layer of the membrane to the inner layer, so that the inner layer has a high concentration of phosphatidylserine and the outer layer has almost none.

Dysfunctional flippases cause cells to die

Flippases have important functions.

If the flippases are disabled when, for example, an enzyme cuts them, many of the phosphatidylserine molecules return to the outer membrane layer.

The presence of phosphatidylserine in the outer membrane layer initiates several processes. One very important one is that they signal to the immune system that the cells must be destroyed.

The immune system’s macrophages detecting phosphatidylserine on the surface of a cell indicates that the macrophages must destroy the cell. Flippases and phosphatidylserine therefore also play an important role in programmed cell death (apoptosis), in which cells self-destruct. Apoptosis is a key event in maintaining healthy tissue.

Phosphatidylserine on the surface of a cell also has a decisive role in blood coagulation.

Phosphatidylserine on the surface of platelets is part of the molecular cascade that ends in blood clotting.

“The flippases are so important, because if they did not exist, all the cellular signalling pathways that include phosphatidylserine would be constantly activated,” explains Jens Peter Andersen.

Mutations in flippases can lead to disease

Since phosphatidylserine is so important in many processes in the body, it is no wonder that dysfunctional flippases can lead to various diseases.

For example, dysfunctional flippases are associated with diseases of the nervous system such as cerebellar ataxia, mental retardation and disequilibrium syndrome (CAMRQ); and Alzheimer’s disease.

The flippases in the liver secure bile transport, and if the flippases do not work, the liver cannot get rid of the bile, which instead accumulates and degrades the liver.

“In previous research, we investigated several pathogenic mutations in the flippases. We could see how changes in the amino acid composition of the flippases make them dysfunctional in transporting phosphatidylserine from the outer to the inner cell membrane,” says Jens Peter Andersen.

Flippases generate electrical current as they move lipids

Improving understanding of the role of flippases in various diseases requires understanding all aspects of their functioning. In the new research, Jens Peter Andersen’s research group investigated whether flippases can create electric current in the cell membranes.

Such current can change the difference in electrical potential between the cell’s exterior and interior, and cells use this difference to control many essential processes.

This electrical potential is required for the cells to perform their many functions.

With the help of partners in Italy, the Danish researchers have succeeded in measuring the electrical discharge emitted by the flippases when they receive energy in the form of ATP, the fuel of cells.

“Our experiments showed that applying ATP to the flippases produced a measurable electrical current. This means that the membrane’s electrical potential changes as the flippases move the lipids, and this is completely new knowledge,” says Jens Peter Andersen.

Mapping the functions of individual amino acids in the flippases

Jens Peter Andersen’s research group has previously investigated the functions of the individual amino acids in the flippases, and this research has shown that, although flippases move relatively large molecules in the form of lipids, they are very similar to ion pumps that merely move small ions.

In 2014, the researchers proposed a hypothesis on how the flippases might look and function, and this hypothesis has recently been confirmed.

This comparison with ion pumps meant that the researchers wanted to investigate whether the flippases also influence the electrical potential of the cell membranes, as the ion pumps do.

“Until our research, no one had imagined that the flippases could generate electrical current and thus affect the cell’s functioning electrically. Now we know that the flippases also affect many pumps and enzymes through electric current, and although we do not yet have an overview of the possible effects, flippases can clearly affect our health in ways we did not know,” says Jens Peter Andersen.

One aspect of the further research by the research group is to determine how the ability of flippases to generate electrical current affects other pumps, ducts and enzymes in a cell membrane and how any mutations in flippases can disrupt the electrical potential and cause disease.

Phosphatidylserine flipping by the P4-ATPase ATP8A2 is electrogenic” has been published in the Proceedings of the National Academy of Sciences of the United States of America. In 2018, the Novo Nordisk Foundation awarded a grant to Jens Peter Andersen for the project Mechanism, Structure and Electrogenicity of the Phospholipid Flippase ATP8A2.

Jens Peter Andersen
Professor
Phospholipid flippases constitute the largest subfamily of P-type ATPases and have in eukaryotic organisms evolved as a central transport system for selective translocation of phospholipids across biological membranes to generate membrane lipid asymmetry, a property essential for numerous cellular processes. The importance of flippases is highlighted by severe neurological disorders and liver diseases caused by flippase dysfunction in humans. The electrogenicity of phospholipid transport by flippases has not previously been explored. We demonstrated that phosphatidylserine translocation by the flippase ATP8A2 generates electrical current, resulting from specific steps in the flippase reaction cycle moving the charged lipid head group between the membrane bilayer leaflets, and that no charged substrate is being countertransported. These findings unravel key features of phospholipid flippases.