Discovery expands what is known about dopamine

Breaking new ground 2. aug 2022 3 min Professor Claus Juul Løland Written by Kristian Sjøgren

Dopamine is not taken up into the neurons of the brain in the way researchers previously thought. The textbooks on dopamine and perhaps other neurotransmitters need to be rewritten, and the discovery may have implications for developing drugs to combat many brain diseases and disorders.

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New research shows that the neurons in the brain do not absorb dopamine in the way that researchers previously thought.

Instead of solely depending on the differences in sodium concentrations across the cell membrane of the neurons, uptake also depends on the concentration of potassium.

The discovery fundamentally expands the understanding of how the brain regulates the availability of dopamine – and perhaps other neurotransmitters. This may affect not only the understanding of various diseases and brain disorders but also how to treat the people who have them.

“Our discovery is essentially a new drug target for people with, for example, schizophrenia or attention-deficit/hyperactivity disorder, both of which can be treated by regulating the availability of dopamine in the brain. In addition, the finding reveals that the same mechanism is present in the regulation of several other neurotransmitters, which may have implications for the treatment of many more mental disorders,” explains a researcher behind the discovery, Claus Juul Løland, Professor, Department of Neuroscience, University of Copenhagen.

The research has been published in Nature Communications.

Ions regulate the uptake of neurotransmitters

The discovery by Claus Juul Løland and colleagues focuses on the dopamine transporter, a protein in the neurons in the brain that ensures the uptake of dopamine from the environment.

When our senses detect something good, such as the taste of chocolate, neurons in the brain are stimulated and release dopamine to the environment. Dopamine affects other neurons, resulting in a sense of motivation or reward. We want more chocolate.

At some point, the effect of dopamine must be terminated so that the neurons can receive a new shot of dopamine, and this is provided by dopamine transporters in the cell membrane of the neurons.

Based on the difference in the concentration of sodium ions on either side of the cell membrane, the transporters facilitate dopamine reuptake into the cells and thereby reset the dopamine signal.

Increasing the effect of dopamine in the brain requires turning off the dopamine transporters; cocaine does this very effectively.

“We have known for many years that dopamine is regulated in this way. The same applies to all the other neurotransmitters, which are also regulated by the specific transporters that use the sodium gradient across the cell membrane to absorb the neurotransmitters like a vacuum cleaner,” says Claus Juul Løland.

Potassium also regulates dopamine

However, a similar protein that transports the neurotransmitter serotonin uses both sodium and potassium to transport it into the cells. A potential drug target could be to decouple the effect of potassium if the aim of treatment is not to turn the transporter on or off but just to adjust the activity a little.

The new results show that potassium also regulates dopamine.

“This is a great discovery, because for the past 40 years we thought that the serotonin transporter was the only one with its activity regulated by the potassium gradient. Since we found that this also applies to dopamine, this may apply to many more neurotransmitters. This expands the opportunity for adjusting the regulation of these neurotransmitters with drugs and thereby treating many diseases,” explains Claus Juul Løland.

Several experiments led to the amazing discovery

The researchers carried out several experiments to elucidate the role of potassium in regulating dopamine in the brain.

The researchers overexpressed the dopamine transporter in the surface of cells and then harvested them so that they could study their effect in a well-controlled cell system.

The researchers used radiolabelled dopamine to monitor how alterations in the concentrations of potassium inside and outside the cells changed how the cells take up the neurotransmitters.

The researchers also studied the activity of the cells and the transporters in detail under a microscope.

Both types of experiments confirmed that the dopamine transporters depend on potassium for regulating the uptake of dopamine.

Indicates novel drug targets

According to Claus Juul Løland, the discovery could strongly influence the treatment of various diseases.

The various transporters are already attractive targets in the drug treatment of many brain diseases and disorders.

Serotonin uptake is a useful target for treating anxiety, depression and post-traumatic stress disorder.

The uptake of GABA, a neurotransmitter, is a useful target for treating epilepsy.

Dopamine uptake is a useful target for treating Parkinson’s disease, attention-deficit/hyperactivity disorder, substance use disorders and schizophrenia.

So far, various challenges have been associated with making drugs that target the various transporters because shutting them down completely is not always suitable. For example, treating Parkinson’s disease, attention-deficit/hyperactivity disorder and schizophrenia with cocaine is not appropriate.

Similarly, shutting down the transporters can cause various side-effects.

For example, several treatments targeting the serotonin transporter lead to weight gain and sexual dysfunction.

However, the new research indicates new options for regulating the uptake of dopamine, so that the dopamine signal no longer needs to be on or off. Perhaps uptake can be increased slightly by simply targeting the ability of the transporter to use potassium as an energy source.

“We have identified the potential for making completely new types of drugs that more selectively regulate the uptake of various neurotransmitters, which depend on the potassium gradient across the cell membrane. Such drugs could probably offer people with many types of mental disorders a whole new form of treatment,” concludes Claus Juul Løland.

The dopamine transporter antiports potassium to increase the uptake of dopamine” has been published in Nature Communications. In 2017, the Novo Nordisk Foundation awarded a grant to Claus Juul Løland for the project "Does K + play a generic role in the substrate transport process of Na + -coupled neurotransmitter transporters?" and in 2019 for the project "Does K + play a generic role in the substrate transport process of Na + -coupled neurotransmitter transporters?".

The main expertise of the Løland Lab is on structure-function relationships in membrane transporters with focus on the Neurotransmitter:Sodium Symport...

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