A Small Protein May Help People with Epilepsy and Other Diseases

Posted by Jerry Carter on June 30th, 2022

For the first time, scientists have elucidated the structure of GABA transporter 1 (GAT-1) using cryo-electron microscopy. The discovery could lead to better new treatments for neurological disorders such as anxiety, autism spectrum disorder, schizophrenia and Parkinson's disease.

In determining the structure of this transporter, one of the smallest proteins ever made, researchers have opened up new avenues to improve drugs for a variety of debilitating diseases, including epilepsy, bipolar disorder, schizophrenia disorders, Parkinson's and Huntington's Diseases, anxiety and autism spectrum disorders.

The gaps between neurons are called synapses, and neurons transmit signals to each other by transmitting neurotransmitters. The GABA molecule (short for gamma-aminobutyric acid) is one of the most common neurotransmitters in the brain.

When a neuron emits gamma aminobutyric acid (GABA), which is sent to nearby neurons via synapses, GABA inhibits the activity of the receiving neuron.

But sometimes things can go wrong and not enough GABA reaches the receiving neuron, which can then become hyperactive, sending too many electrical impulses. This can lead to some debilitating effects, including seizures.

Fortunately, certain drugs can help release GABA by blocking a protein called GAT-1 (short for GABA transporter 1). GAT-1 is responsible for recycling released GABA into releasing neurons.

Once the GAT-1 inhibitor tiagabine (brand name Gabitril) reduces GABA cycling, it leaves more GABA in the synapse, reducing the activity of the receiving neurons.

While tiagabine may be effective, the exact way in which it interacts with GAT-1 to inhibit GABA recycling has been a mystery. Understanding their interactions could help researchers one day create more effective drugs.

To solve this mystery and see exactly how tiagabine binds to GAT-1, researchers at USC Dornsife College of Liberal Arts used a highly advanced cryo-electron microscope. The technique involves freezing molecules at extremely low temperatures near where atoms and molecules completely stop moving, then imaging them with an electron microscope.

The study's lead author Cornelius Gati and a team of scientists at USC Dornsife observed GAT-1 in complex with tiagabine and used cryo-electron microscopy to visualize the interaction of the two.

Gati, assistant professor of biological sciences and chemistry at USC Dornsife, said: "Previous understanding of this inhibitor (tiagabine) was based purely on biochemical studies and did not provide any details on the atomic scale. We can now determine for sure the specific part of the drug that interacts with the protein."

The new findings suggest a previously unknown mechanism by which GAT-1 is inhibited, Gati said, in that when tiagabine binds to GAT-1, the overall shape of the protein changes.

The highly detailed information revealed by this study could help researchers improve drugs or develop new treatments for diseases associated with GABA-controlled neurons.

"These findings have direct implications for the whole of pharmacology, not only in the treatment of epilepsy but in many other diseases," Gati said, adding that the results point to further research.

"We have a feeling that this newly revealed mechanism is much more general than currently thought, so we will first investigate this by using structurally similar inhibitors, and then expand the search to other molecules."

Gati also noted that using cryo-EM to resolve the structure of interacting molecules has proven extremely challenging—GAT-1 is one of the smallest proteins resolved with the technique and is difficult to visualize even with such advanced technology.

Their success, he said, will inspire scientists at USC and other institutions to determine the structure of other challenging membrane proteins, leading to further understanding of drug-protein interactions and improved treatments.