Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors - Groupe Microscopie Electronique et Méthodes / Methods and Electron Microscopy Group (IBS-MEM)
Article Dans Une Revue Nature Structural and Molecular Biology Année : 2024

Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors

Uriel López-Sánchez
Lucy Kate Ladefoged
Benny Bang-Andersen
Birgit Schiøtt
Guy Schoehn

Résumé

Vortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate the drug’s molecular mechanism of operation at serotonin 5-HT3 receptors (5-HT3R), which features two mysterious properties: VTX acts differently on rodent and human 5-HT3R; VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist boundlike state of the human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism
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hal-04735636 , version 1 (14-10-2024)

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Uriel López-Sánchez, Lachlan Jake Munro, Lucy Kate Ladefoged, Anders Juel Pedersen, Christian Colding Brun, et al.. Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors. Nature Structural and Molecular Biology, 2024, 31 (8), pp.1232-1242. ⟨10.1038/s41594-024-01282-x⟩. ⟨hal-04735636⟩
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