New findings on how stimulant-like compounds modulate receptor activity

Two recent studies supported by SciLifeLab research infrastructure (Cryo-EM) provide complementary findings on how stimulants modulate key receptors. The two studies were published in British Journal of Pharmacology and Science Advances. 

The combined studies present new results showing how stimulant-like compounds such as amphetamines and their natural analogues can influence a fundamental group of proteins called ligand-gated ion channels. These channels are involved in electrical signaling in both the nervous system and other tissues, including the gut.

Using bacteria to understand brain receptor function

In one study, they used a bacterial model receptor known as sTeLIC to examine how derivatives of psychostimulants affect receptor activity. These compounds, including brominated versions of phenylethylamine, were found to enhance channel function in electrophysiology experiments. The researchers also determined high-resolution structures of the channel using cryo-electron microscopy and X-ray crystallography.

“It was really exciting to see how these small molecules could fine-tune activity through this lesser-known site. I’m hoping this sparks new ideas about how these channels work—and how we might design better treatments for neurological disorders in the future,” says Emilia Karlsson, SciLifeLab researcher and PhD student at Stockholm University

A key finding was the identification of a small pocket, called the vestibular site, that only becomes accessible when the receptor is in an open, active state. Binding at this site appears to stabilize the open form of the channel, which helps explain how these molecules enhance activity. While the study focused on a bacterial system, the results may help explain similar mechanisms in human receptors. Particularly those related to serotonin.

Mapping drug effects in serotonin receptors

In a separate study, the researchers investigated mammalian serotonin-3 receptors, which are involved in functions such as mood regulation, digestion and sleep. Using a combination of computer simulations, mutagenesis and electrophysiology, they identified a similar vestibular site that interacts with stimulant-like compounds.

This site shares features with the bacterial receptor. Suggesting that aspects of drug sensitivity may have evolved early and been conserved. The simulation-driven approach helped clarify how modulator binding could stabilize receptor activity by affecting contacts between subunits.

This second study highlights a previously underexplored drug target in serotonin receptors. If confirmed in further studies, it could support the development of more selective treatments for psychiatric and gastrointestinal conditions. Potentially reducing the amount of side effects.

“Our research will aid the development of more effective, targeted treatments for psychiatric disorders and gut diseases, offering patients new hope and improved options for managing symptoms and side effects,” says KTH researcher Nandan Haloi.

Vestibular modulation by stimulant derivatives in a pentameric ligand-gated ion channel, DOI: 10.1111/bph.70011

Discovering cryptic pocket opening and binding of a stimulant derivative in a vestibular site of the 5-HT3A receptor, DOI: 10.1126/sciadv.adr0797

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