Antidepressant drugs act by directly binding to TRKB neurotrophin receptors
Authors: Iseline Cardon
Vera Kovaleva
Mykhailo Girych
Mart Saarma
Ilpo Vattulainen
Timo Petteri Piepponen
Hanna Antila
Tomasz Rog
Clive R Bramham
Anna Steinzeig
Giray Enkavi
Eero Castr√©n
Liina Laukkanen
Sari E Lauri
Cecilia A Brunello
Sudarshan Patil
Cecilia Cannarozzo
Claus Normann
Caroline Biojone
Katja Kaurinkoski
Stefan Vestring
Cassiano R A F Diniz
Plinio C Casarotto
Senem M Fred
Rafael Moliner
Tsvetan Serchov
Madhusmita Pryiadrashini Sahu
Frederike Winkel
Journal: Cell (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: BDNF; antidepressant; cholesterol; fluoxetine; ketamine
Affiliations: Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Department of Physics, University of Helsinki, Helsinki, Finland., Institute of Biotechnology-HILIFE, University of Helsinki, Helsinki, Finland., Department of Biomedicine and KG Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway., Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Ribeir√£o Preto Medical School, University of S√£o Paulo, S√£o Paul, Brazil., Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Brain Master Program, Faculty of Science, Aix-Marseille Universit√©, Marseille, France; Department of Psychiatry, University of Regensburg, Regenburg, Germany., Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Basics in Neuromodulation (NeuroModul Basics), University of Freiburg, Freiburg, Germany., Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland., Department of Physics, University of Helsinki, Helsinki, Finland; Computational Physics Laboratory, Tampere University, Tampere, Finland., Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland. Electronic address: .

Abstract:  It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery. 

Retracted: No

PubPeer comments:
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 There are interesting replies to this tweet, and in the commentary of Derek Lowe s blog. https: twitter.com Dereklowe status 1362811116393529347 https: blogs.sciencemag.org pipeline archives 2021 02 19 how-antidepressants-work-at-last , 
 We have researched this topic for years and were perplexed by the findings of this paper in question. We just published a preprint of our findings that are in a bit of a contrast with this one. If interested, you can find it here: https: www.biorxiv.org content 10.1101 2021.08.30.458151v1 ,