Researchers identify the basic principles of serotonin transport in nerve cells

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Drugs known as antidepressants target the serotonin transporter in nerve cells and are among the most prescribed drugs worldwide, but are sometimes associated with significant side effects. As part of a study, a research team led by Thomas Stockner of Meduni Vienna identified the basic principles of serotonin transport and thus created a potential basis for the development of novel drugs with improved selectivity and fewer unwanted effects. The results were recently published in the renowned scientific journal “Nature Communications”.

While the desired effects of drugs are manifested by interactions with relevant target structures, unwanted side effects are often due to lack of selectivity and hence interactions with other target structures. Accordingly, developing drugs that can discriminate between different physiologically relevant targets (such as transporters and receptors) is one of the research challenges. A team led by Ralf Gradisch, under the supervision of Thomas Stockner from the Center for Physiology and Pharmacology in Vienna, Austria, set out to find ways to increase selectivity for the serotonin transporter while reducing interactions with other targets of nerve cells in the brain. In collaboration with the research group of Marko Mihovilovic from the Institute of Applied Synthetic Chemistry at TU Vienna, the researchers discovered the basic principles by which the serotonin transporter recognizes the neurotransmitter serotonin through the synthesis of serotonin-related molecules and decodes the transport requirements. This messenger is of substance.

Controlling emotions with serotonin

Neurotransmitters, also known as messenger substances, act as “delivery services” for information between nerve cells (neurons). The neurotransmitter serotonin, also known as the “happy hormone,” is associated with positive emotions, as it plays an important role in regulating mood and calmness. Accordingly, low serotonin levels are associated with mental illnesses such as depression, anxiety, and obsessive-compulsive disorder. Drugs that target the serotonin transporter are among the most commonly prescribed drugs worldwide. Blocking the serotonin transporter with serotonin reuptake inhibitors increases the concentration of the neurotransmitter in the so-called synaptic cleft between nerve cells and helps reduce the disease burden in patients.

The steps are explained in minute detail

The complex steps required for serotonin transport were described in the study at the single-molecule level, i.e. down to the smallest detail.

“It was the appropriate combination of chemical synthesis with experimental and computational pharmacology methods that made the results of this study possible.”


Ralph Gradish, first author

“Our findings reveal the key forces and interactions that are at work here to initiate serotonin transport. This may form the basis of new types of molecules and, in turn, allow the development of drugs that can more precisely target the transporter than what is currently determined,” the main Investigator Thomas Stockner said, summarizing the relevance of the findings.

Source:

Journal Reference:

Gradish, R., etc (2024). The ligand coupling mechanism of the human serotonin transporter distinguishes substrate from inhibitor. Nature communication. doi.org/10.1038/s41467-023-44637-6.



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