Research can lead to new therapies for mental disorders

Disease and treatment 5. mar 2021 3 min Professor Poul Nissen, Assistant Professor Azadeh Shahsavar Written by Kristian Sjøgren

Danish and international researchers have mapped the structure of an amino acid transporter in the brain that may be an important target for developing therapies to treat numerous disorders, including schizophrenia.

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For many years, researchers have been investigating whether they can alter the transport of glycine, a small amino acid, in the brain.

Glycine has a key role in activating the N-methyl-d-aspartate (NMDA) receptor, which is implicated in the pathophysiology of schizophrenia.

NMDA needs glycine to function optimally, and things go wrong when glycine is not present in sufficient quantities.

Delaying the uptake of glycine into the brain’s neurons pharmaceutically, thereby increasing the availability of glycine for NMDA, could be very potent in treating schizophrenia.

This idea has been around for 20 years, but researchers have encountered several bumps in the road and no drug has yet emerged, although some candidates have come close.

However, there may be light at the end of the tunnel. An international team including researchers at Aarhus University has now mapped the structure of the human glycine transporter (GLyT1). This enables researchers to determine much more easily how they can affect this transport and perhaps relieve the symptoms of schizophrenia.

“There is promising pharmaceutical potential in regulating the levels of glycine in the brain. Mapping the structure of GLyT1 enables more targeted research for developing drugs for this debilitating cognitive disorder,” explains co-author Poul Nissen, Department of Molecular Biology and Genetics, Aarhus University and Director, Danish Research Institute of Translational Neuroscience – DANDRITE, Nordic EMBL Partnership of Molecular Medicine.

The research results have been published in Nature.

Glycine levels in the brain are tightly regulated

Glycine is the smallest amino acid and is part of the structure of many proteins. But glycine is also a neurotransmitter involved in the signalling between the neurons in the brain.

Glycine can both stimulate and inhibit these neurons and thus plays a key role in the brain’s complex functions, including cognition.

The glycine signal between the synapses of the neurons is inhibited by the uptake of glycine into the cells through GlyT1, which is the main regulator of the levels of glycine in the brain and inhibits its uptake.

Specifically in relation to schizophrenia and NMDA, however, GlyT1 not absorbing all glycine immediately may be positive, since this can reduce the symptoms of schizophrenia by prolonging neurotransmitter signalling.

Glycine transporters also present in blood

Although researchers have known for many years about the pharmaceutical potential of regulating glycine uptake into the neurons in the brain, there are very specific reasons why a successful drug has not emerged.

One major problem is that GlyT1 is present in both the brain and other cells, including red blood cells, with glycine playing a key part in the biosynthesis of haemoglobin, which transports oxygen.

Although clinical trials with drug candidates for treating people with schizophrenia have shown promising signs in early clinical trials, they have failed in Phase III clinical trials when administered at a reduced dose to avoid blood problems.

The drug failed to show efficacy at this dose, and the dream of being able to cure schizophrenia was not fulfilled.

However, researchers have not given up.

“Differences may still be identified between the glycine transport in the brain cells and in the blood cells. We can use such differences to design drug candidates that only affect GlyT1 in the brain and not in the blood,” says co-author Azadeh Shahsavar, Assistant Professor, Department of Molecular Biology and Genetics, Aarhus University.

Mapping the structure of the transporter with powerful X-rays

Azadeh Shahsavar, Poul Nissen and colleagues mapped the three-dimensional structure of GlyT1 by using serial synchrotron crystallography, which sends enormously powerful X-rays through microcrystals of GlyT1.

For the first time, the researchers determined the three-dimensional structure of GlyT1 in its inhibited state with a drug candidate bound to the transporter by recording the diffraction data from hundreds of microcrystals.

They can use this discovery to more accurately design other compounds that can interact with the protein in the same way but with new properties.

“We can see which parts of the protein are affected when the inhibitor is bound and how the binding site is located in relation to the cell membrane. We can also see where on the inhibitor we can make changes that produce the altered properties,” explains Poul Nissen.

Transporter inhibited on the intracellular side

The researchers found that the binding site for inhibitors on GlyT1 is on the intracellular side of the cell, which may have prospects for developing new drug candidates.

This means that inhibiting GlyT1 to increase the levels of glycine requires that a given inhibitor cross the cell membrane to achieve the inhibitory effect.

This becomes important for drug developers, because compounds might be designed that can only diffuse across the synaptic cell membrane but not across blood cells.

Such compounds would initiate the antischizophrenic effect on NMDA from elevated levels of glycine but would not negatively affect the formation of red blood cells.

“We are investigating this in a new project, and we hope to get a biotechnology company involved in the idea,” says Azadeh Shahsavar.

Structural insights into the inhibition of glycine reuptake” has been published in Nature. In 2018, the Novo Nordisk Foundation awarded a grant to Poul Nissen for the project Structure Determination of the Human Glycine Transporter hGlyT1.

Poul Nissen has a background in crystallographic studies of translation factors and the ribosome. He became interested in P-type ATPases when he retur...

The Nissen group investigates the structure and molecular mechanisms of membrane transport processes, receptors, and biomembrane ultrastructure. Activ...

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