Year: 2026
Type: article
Abstract: The transient receptor potential melastatin 3 (TRPM3) channel is a key mediator of peripheral pain signaling, and pathogenic mutations in TRPM3 are linked to neurodevelopmental delay and epilepsy. Despite the therapeutic promise of TRPM3 modulators, the molecular mechanisms by which ligands modulate channel gating remain poorly understood. Here, we combine cryo-electron microscopy (cryo-EM) with functional analyses to characterize a promiscuous ligand-binding pocket formed by transmembrane helices S1–S4. This pocket accommodates several chemically diverse plant-derived and synthetic agonists and antagonists. We show stereoselectivity of TRPM3 for the (R)-enantiomer of the flavonoid antagonist isosakuranetin and the (R)-enantiomer of the synthetic agonist CIM0216. Mutations within this pocket—including variants identified in patients —alter ligand affinity and, in some cases, invert the functional outcome of ligand binding. These findings reveal the stereoselectivity and functional plasticity of the TRPM3 ligand-binding pocket, highlighting how subtle changes in the molecular interactions can produce divergent effects on channel gating, with important ramifications for TRPM3-targeted drug development and therapy. TRPM3 mediates pain, and mutations in the TRPM3 gene cause neurodevelopmental delay and epilepsy. Here, the authors use cryo-EM and functional studies to define an S1–S4 pocket that binds diverse ligands with stereoselective and mutation-dependent effects on channel gating.
Source: Nature Communications
Authors: Bahar Bazeli, Alexander V. Shkumatov, Stephan Schenck, Jean-Christophe Vanherck, Annelies Janssens, Stéphane A. H. Spieser, Damien Marchand, Robbe Roelens, Patrick Chaltin, Arnaud Marchand, Joris Vriens, Thomas Voets, Janine D. Brunner
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: TRPM3 - a key regulator of inflammatory pain, TRP - Tackling the Roots of Pain, Pharmacological targeting of the heat-activated TRP channel triad for pain relief, The role of TRPM3 in the development of pathological pain - from the periphery to the brain, A kinetic, high-throughput cellular screening system (Plate Imaging Reader) for the "real time" monitoring of dynamic intracellular Ca2+ signals in living cells, G5311267937, G6430960210
OpenAlex ID: W7147444689