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Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT 3 receptors.
- Source :
-
Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Aug; Vol. 31 (8), pp. 1232-1242. Date of Electronic Publication: 2024 May 02. - Publication Year :
- 2024
-
Abstract
- Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT <subscript>3</subscript> receptor (5-HT <subscript>3</subscript> R), which features two properties: VTX acts differently on rodent and human 5-HT <subscript>3</subscript> R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT <subscript>3</subscript> R and an agonist-bound-like state of human 5-HT <subscript>3</subscript> R, in line with the functional profile of the drug. We report four human 5-HT <subscript>3</subscript> R 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.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Subjects :
- Humans
Animals
Mice
Piperazines pharmacology
Piperazines chemistry
Sulfides chemistry
Sulfides pharmacology
Molecular Dynamics Simulation
HEK293 Cells
Vortioxetine pharmacology
Vortioxetine chemistry
Receptors, Serotonin, 5-HT3 metabolism
Receptors, Serotonin, 5-HT3 chemistry
Antidepressive Agents pharmacology
Antidepressive Agents chemistry
Cryoelectron Microscopy
Subjects
Details
- Language :
- English
- ISSN :
- 1545-9985
- Volume :
- 31
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature structural & molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 38698207
- Full Text :
- https://doi.org/10.1038/s41594-024-01282-x