Scientists discover how 5-HT1A receptor shapes brain signalling

In a new discovery, researchers at the Icahn School of Medicine at Mount Sinai have developed new insights into how a critical brain receptor works at the molecular level. This could eventually lead to the development of more targeted antidepressant medications.

The study, published in Science Advances, focuses on the 5-HT1A serotonin receptor – a major component in regulating mood and a common target for traditional antidepressants. Despite its clinical importance, this receptor has remained poorly understood, with many of its molecular and pharmacological properties hugely understudied – until now.

A molecular ‘control panel’ for brain function

“This receptor is like a control panel that helps manage how brain cells respond to serotonin, a key chemical involved in mood, emotion and cognition,” says senior author Dr Daniel Wacker, Assistant Professor of Pharmacological Sciences and Neuroscience, at the Icahn School of Medicine at Mount Sinai. “Our findings shed light on how that control panel operates – what switches it flips, how it fine-tunes signals and where its limits lie. This deeper understanding could help us design better therapies for mental health conditions like depression, anxiety and schizophrenia.”

Using new lab techniques, the research team found that the 5-HT1A receptor is inherently wired to favour certain cellular signalling pathways over others – regardless of the drug used to target it. However, drugs can still influence the strength with which those pathways are activated.

Cryo-EM sheds light on key interactions

To explore these mechanisms in more detail, the researchers combined experiments in lab-grown cells with high-resolution cryo-electron microscopy (cryo-EM) – an imaging technology that reveals molecular structures at near-atomic resolution. Their work focused on how various drugs activate the 5-HT1A receptor and how the receptor interacts with internal signalling proteins known as G proteins.

Different signalling pathways controlled by the 5-HT1A receptor are linked to different aspects of mood, perception and pain. As scientists better understand which pathways are activated, they can more precisely design drugs that treat specific symptoms or conditions without unwanted side effects.

“Our work provides a molecular map of how different drugs ‘push buttons’ on this receptor – activating or silencing specific pathways that influence brain function,” says study first author Dr Audrey L Warren, a former student in Dr Wacker’s lab who is now a postdoctoral researcher at Columbia University. “By understanding exactly how these drugs interact with the receptor, we can start to predict which approaches might lead to more effective or targeted treatments and which ones are unlikely to work. It’s a step toward designing next-generation therapies with greater precision and fewer side effects.”

A hidden ‘co-pilot’ molecule

In a surprising finding, the researchers discovered that a phospholipid – a type of fat molecule found in cell membranes – plays a major role in steering the receptor’s activity, almost like a hidden co-pilot. This is the first time a role like this has been observed among the more than 700 known receptors of this type in the human body.

While current antidepressants often take weeks to work, scientists hope this new understanding of 5-HT1A signalling could help explain those delays and lead to faster-acting alternatives.

“This receptor may help explain why standard antidepressants take long to work,” says Dr Wacker. “By understanding how it functions at a molecular level, we have a clearer path to designing faster, more effective treatments, not just for depression, but also for conditions like psychosis and chronic pain. It’s a key piece of the puzzle.”

Looking ahead: from the lab to clinic

Next, the researchers plan to dig deeper into the role of the phospholipid ‘co-factor’ and to test how their lab-based findings hold up in more complex experiments. They are also working on turning these discoveries into real-world compounds that could become future psychiatric medications, building on their earlier success with drug candidates derived from psychedelics.

This breakthrough not only broadens scientific understanding of brain signalling but could also enable the design of mental health treatments that are faster, more precise and have fewer side effects.