Researchers from VIB, VUB and KU Leuven have identified a small binding site, a molecular “keyhole”, in the TRPM3 ion channel, a key sensor in pain signaling. TRPM3 is also associated with rare neurodevelopmental disorders and epilepsy. In a recent study published in nature communicationsresearchers discovered that even small changes in this keyhole can fundamentally switch the channel’s behavior, and explained how certain mutations can reverse the drug’s effects.
If you have a mirror image of the key, or if you make very small changes to the key or keyhole, the door can suddenly open and close. ”
Professor Thomas Votz, co-leader of the study and group leader at VIB and the University of Leuven
The research also resulted from a strong collaboration between the Leuven center and VUB’s Janine Brunner, with Alexander Shukumatov and Stefan Schenck also co-lead authors.
Overactivation of TRPM3 is associated with neurodevelopmental problems and epilepsy. Therefore, therapeutic strategies have been explored to inhibit this channel, and one of the most common strategies uses the plant-derived flavonoid isosakuranetin. They observed that it has two mirror image shapes, S and R. Surprisingly, only the R shape fits into the pocket and blocks the channel.
“We discovered that the active form of isosacranetin is R, not S,” said Bahar Bazeli, co-lead author of the study. “R is a strong inhibitor of the channel, while S is ineffective.”
Researchers discovered even more. A surprising finding is that patient-derived mutations in this pocket can alter drug response.
“Small changes in this pocket can also influence the direction and efficacy of the effect,” explains Baselli. “It’s possible to turn an antagonist into an agonist and vice versa. We know that patients with these particular mutations shouldn’t take the drugs that everyone else is using. The drugs won’t work for them and will only cause side effects with no benefit.”
In other words, R will be disabled or trigger the channel instead of suppressing it. This plasticity has direct clinical implications, as some of the TRPM3 variants associated with epilepsy reside in this very pocket, explaining why certain drugs do not work in these patients.
Another recent study published in cell report medicinefocused on how TRPM3 contributes to trigeminal neuralgia, one of the most severe pain diseases.
Trigeminal neuralgia is caused by injury or compression of the trigeminal nerve in the face. Researchers found that nerve injury and inflammation increased TRPM3 activity, causing facial pain neurons to become overexcited.
“Trigeminal neuralgia is one of the worst pain syndromes. It’s so painful that people call it a suicide disease,” says Professor Thomas Votz. “We showed that inhibition of TRPM3 works surprisingly well in animal models.”
These findings were supported by genetic data. Certain TRPM3 gene variants, which may make the channel more active, are significantly more common in trigeminal neuralgia patients than in the general population. This suggests a genetic predisposition due to TRPM3 and, in conjunction with the above studies, shows why some patients are resistant to common treatments. Different variants cause different keyholes to the drug and prevent the desired analgesic effect.
Taken together, these studies highlight how important finding the master key to TRPM3 is for controlling pain and improving neurological health. Understanding exactly how molecules fit into this lock will allow drug developers to design better “keys” that are more powerful and selective for treating TRPM3-related conditions. Researchers are now designing variant-specific TRPM3 blockers to translate these findings into personalized pain treatments.
“Knowing exactly how molecules fit into this lock will be very helpful in developing better and more specific drugs. We are currently working on developing keys for an even better fit,” concludes Voets. “These studies open the door to personalized pain medications, allowing physicians to tailor treatment based on a patient’s TRPM3 ‘keyhole’.”
Ultimately, unlocking this molecular keyhole could lead to effective new treatments for chronic pain syndromes, neurodevelopmental disorders, and epilepsy.
sauce:
Flemish Institute of Biotechnology
Reference magazines:
Basel, B. Others. (2026). Stereoselectivity and functional plasticity of the common ligand-binding pocket of TRPM3. nature communications. DOI: 10.1038/s41467-026-71226-0. https://www.nature.com/articles/s41467-026-71226-0
