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Molecular mechanisms of serotonin 5-HT1A receptor revealed: a step towards new antidepressants
Last reviewed: 03.08.2025
Researchers at the Icahn School of Medicine at Mount Sinai have taken an important step toward the next generation of antidepressants and antipsychotics by uncovering the molecular mechanisms of one of the brain's key receptors, the 5-HT1A serotonin receptor.
In a paper published in the journal Science Advances, the team detailed the structural features of the 5-HT1A receptor and its interactions with G-protein signaling proteins that determine which intracellular activation pathways are preferred when binding to different drugs. This receptor is responsible for regulating mood, emotion, and cognitive processes, and is also a target for traditional antidepressants and new psychedelic therapies.
"The 5-HT1A receptor is like a control panel that regulates how brain cells respond to serotonin, the main mood neurotransmitter," explains lead author Dr. Daniel Wacker. "Our findings show exactly how this control panel works: which switches it turns on, how it tunes signals, and where its limits are. This could help us design drugs that are more targeted and have fewer side effects."
The uniqueness of the study is that the team has shown for the first time that the receptor by default tends to activate certain cellular signaling pathways regardless of the drug. At the same time, different drugs can enhance or weaken the activation of these pathways. For example, the antipsychotic asenapine (Saphris) showed a selective effect on a specific pathway due to weak activity on the receptor.
Using advanced techniques, including high-resolution cryo-electron microscopy, the scientists visualized how the receptor binds to G proteins and how different drugs affect this process. One of the most surprising discoveries was the role of phospholipid, a fatty molecule in the cell membrane that acts as a "hidden co-pilot" directing the receptor's activity. This is the first time such a role has been established for this class of receptors.
Understanding the mechanics of 5-HT1A may explain why traditional antidepressants take weeks to take effect. This new understanding of the receptor opens up the prospect of creating faster, more effective drugs that could be useful not only for depression, but also for psychosis and chronic pain.
"We are only at the beginning of the journey, but these results already provide a clear understanding of how we can create next-generation drugs with high specificity and fewer side effects," concludes Dr. Wacker.
Going forward, the team plans to further explore the role of phospholipid, test their findings in more complex models, and begin developing new drugs based on these molecular data, including promising candidates from the psychedelic group.