Electric switches in our brain need lipids

Our brain cells, and more specifically the channel proteins in the cell wall, need lipids – or fat – to function properly. These are the findings of an international study led by the Laboratory of Structural Neurobiology at KU Leuven. The researchers identified the structure of these proteins in the presence of a lipid molecule at the atomic level for the first time.

The membrane – or cell wall – of a living brain cell houses thousands of proteins. An important class of membrane proteins are ion channels. These are responsible for the communication between the cell and the outside world. Ion channels are microscopically small pores that can open and close, allowing ions – charged particles – to flow in and out of the cell.

The ion channel that reacts to the neurotransmitter gamma-aminobutyric acid (GABA) consists of five subunits (in blue). The opening in the middle is the pore through which ions flow in and out of the cell. The green circle in the middle is a sodium ion. The yellow circles on the bottom right are lipid molecules. |© KU Leuven – Chris Ulens. The authors acknowledge first publication of this image in Nature Chemical Biology.

As such, ion channels are basically electric switches with an on/off button. Controlling the switch requires a key. In our brains, this key is a neurotransmitter: a chemical substance that binds to the ion channel, sending the message to open or close the channel gate. An example of such a neurotransmitter is gamma-aminobutyric acid (GABA). If this neurotransmitter binds to the ion channel, it slows the effect of other brain cells. Sedatives and hypnotics, such as diazepam or zolpidem, make use of this function by strengthening the effect of the neurotransmitter.

Until recently, little was known about detailed lipid interactions of GABA-activated channels, says Professor Chris Ulens of the Laboratory of Structural Neurobiology. “The human ion channel is a complex protein and we were not yet able to fully map it with X-ray crystallography, a standard technique used to study structures. That’s why we’re using the ion channel of a bacteria instead of the human one. The ion channel of a bacteria is really a simplified version of our ion channel, making it technically easier to analyse its structure.”

Surprisingly, this technique showed that the bacterial GABA ion channel also houses a lipid or fat. “It’s one of the bacterial counterparts of our cholesterol. Fats such as cholesterol are mostly known as a potential cause for cardiovascular disorders. Our study, however, shows that the GABA ion channel needs lipids to function properly, just as you need a small amount of oil to lubricate a chain, for instance. The lipids ensure that the ion channel is able to switch from one state (open or closed) to the other.”

This finding opens up perspectives for the development of new medicines based on fat molecules. “An interesting research avenue is related to that of sedatives: medicines that use used for anaesthesia, for instance.”


Click here to read the study in Nature Chemical Biology (DOI: 10.1038/s41589-019-0369-4).

This research was funded by the Research Foundation – Flanders (FWO), the Flemish government agency for Innovation by Science and Technology (IWT), and KU Leuven.

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