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

Uriel López-Sánchez; Lachlan Jake Munro; Lucy Kate Ladefoged; Anders Juel Pedersen; Christian Colding Brun; Signe Meisner Lyngby; Delphine Baud; Céline Juillan-Binard; Miriam Grønborg Pedersen; Sarah C.R. Lummis; Benny Bang-Andersen; Birgit Schiøtt; Christophe Chipot; Guy Schoehn; Jacques Neyton; Francois Dehez; Hugues Nury; Anders S. Kristensen

doi:10.1038/s41594-024-01282-x

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

Uriel López-Sánchez, Lachlan Jake Munro, Lucy Kate Ladefoged, Anders Juel Pedersen, Christian Colding Brun, Signe Meisner Lyngby, Delphine Baud, Céline Juillan-Binard, Miriam Grønborg Pedersen, Sarah C.R. Lummis, Benny Bang-Andersen, Birgit Schiøtt, Christophe Chipot, Guy Schoehn, Jacques Neyton, Francois Dehez, Hugues Nury^*, Anders S. Kristensen^*

^*Corresponding author af dette arbejde

Institut for Kemi

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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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-HT₃ receptor (5-HT₃R), which features two properties: VTX acts differently on rodent and human 5-HT₃R, 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-HT₃R and an agonist-bound-like state of 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.

Originalsprog	Engelsk
Tidsskrift	Nature Structural and Molecular Biology
Vol/bind	31
Nummer	8
Sider (fra-til)	1232-1242
Antal sider	11
ISSN	1545-9993
DOI	https://doi.org/10.1038/s41594-024-01282-x
Status	Udgivet - aug. 2024

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Author Correction: Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors (Nature Structural & Molecular Biology, (2024), 10.1038/s41594-024-01282-x)
López-Sánchez, U., Munro, L. J., Ladefoged, L. K., Pedersen, A. J., Brun, C. C., Lyngby, S. M., Baud, D., Juillan-Binard, C., Pedersen, M. G., Lummis, S. C. R., Bang-Andersen, B., Schiøtt, B., Chipot, C., Schoehn, G., Neyton, J., Dehez, F., Nury, H. & Kristensen, A. S., jul. 2024, I: Nature Structural and Molecular Biology. 31, 7, s. 1145 1 s.
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López-Sánchez, U., Munro, L. J., Ladefoged, L. K., Pedersen, A. J., Brun, C. C., Lyngby, S. M., Baud, D., Juillan-Binard, C., Pedersen, M. G., Lummis, S. C. R., Bang-Andersen, B., Schiøtt, B., Chipot, C., Schoehn, G., Neyton, J., Dehez, F., Nury, H., & Kristensen, A. S. (2024). Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT₃ receptors. Nature Structural and Molecular Biology, 31(8), 1232-1242. https://doi.org/10.1038/s41594-024-01282-x

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abstract = "Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug{\textquoteright}s molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, 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-HT3R and an agonist-bound-like state of 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.",

author = "Uriel L{\'o}pez-S{\'a}nchez and Munro, {Lachlan Jake} and Ladefoged, {Lucy Kate} and Pedersen, {Anders Juel} and Brun, {Christian Colding} and Lyngby, {Signe Meisner} and Delphine Baud and C{\'e}line Juillan-Binard and Pedersen, {Miriam Gr{\o}nborg} and Lummis, {Sarah C.R.} and Benny Bang-Andersen and Birgit Schi{\o}tt and Christophe Chipot and Guy Schoehn and Jacques Neyton and Francois Dehez and Hugues Nury and Kristensen, {Anders S.}",

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doi = "10.1038/s41594-024-01282-x",

language = "English",

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López-Sánchez, U, Munro, LJ, Ladefoged, LK, Pedersen, AJ, Brun, CC, Lyngby, SM, Baud, D, Juillan-Binard, C, Pedersen, MG, Lummis, SCR, Bang-Andersen, B, Schiøtt, B, Chipot, C, Schoehn, G, Neyton, J, Dehez, F, Nury, H & Kristensen, AS 2024, 'Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT₃ receptors', Nature Structural and Molecular Biology, bind 31, nr. 8, s. 1232-1242. https://doi.org/10.1038/s41594-024-01282-x

Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT₃ receptors. / López-Sánchez, Uriel; Munro, Lachlan Jake; Ladefoged, Lucy Kate et al.
I: Nature Structural and Molecular Biology, Bind 31, Nr. 8, 08.2024, s. 1232-1242.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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AU - Pedersen, Anders Juel

AU - Brun, Christian Colding

AU - Lyngby, Signe Meisner

AU - Baud, Delphine

AU - Juillan-Binard, Céline

AU - Pedersen, Miriam Grønborg

AU - Lummis, Sarah C.R.

AU - Bang-Andersen, Benny

AU - Schiøtt, Birgit

AU - Chipot, Christophe

AU - Schoehn, Guy

AU - Neyton, Jacques

AU - Dehez, Francois

AU - Nury, Hugues

AU - Kristensen, Anders S.

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AN - SCOPUS:85191981558

SN - 1545-9993

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

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

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Author Correction: Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors (Nature Structural & Molecular Biology, (2024), 10.1038/s41594-024-01282-x)

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