Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT 3 receptors
Preprint
Abstract
Summary: 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-HT 3 receptors (5-HT 3 R), which features two mysterious properties: VTX acts differently on rodent and human 5-HT 3 R; 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-HT 3 R and an agonist bound-like state of the human 5-HT 3 R, in line with the functional profile of the drug. We report four human 5-HT 3 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.Keywords
This publication has 60 references indexed in Scilit:
- The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slicesBrain Research, 2018
- Expression, Biochemistry, and Stabilization with Camel Antibodies of Membrane Proteins: Case Study of the Mouse 5-HT3 Receptor2017
- Treatment of cognitive dysfunction in major depressive disorder—a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetineEuropean Journal of Pharmacology, 2015
- CHARMM-GUIMembrane Buildertoward realistic biological membrane simulationsJournal of Computational Chemistry, 2014
- Large scale expression and purification of the mouse 5-HT3 receptorBiochimica et Biophysica Acta (BBA) - Biomembranes, 2013
- 5-HT3 receptors: potential of individual isoforms for personalised therapyCurrent Opinion in Pharmacology, 2011
- CHARMM‐GUI: A web‐based graphical user interface for CHARMMJournal of Computational Chemistry, 2008
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water modelsJournal of Computational Chemistry, 1992
- Rattle: A “velocity” version of the shake algorithm for molecular dynamics calculationsJournal of Computational Physics, 1983