Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.

Autor:	Casarotto PC; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Girych M; Department of Physics, University of Helsinki, Helsinki, Finland., Fred SM; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Kovaleva V; Institute of Biotechnology-HILIFE, University of Helsinki, Helsinki, Finland., Moliner R; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Enkavi G; Department of Physics, University of Helsinki, Helsinki, Finland., Biojone C; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Cannarozzo C; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Sahu MP; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Kaurinkoski K; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Brunello CA; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Steinzeig A; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Winkel F; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Patil S; Department of Biomedicine and KG Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway., Vestring S; 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., Serchov T; Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Diniz CRAF; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paul, Brazil., Laukkanen L; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland., Cardon I; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Brain Master Program, Faculty of Science, Aix-Marseille Université, Marseille, France; Department of Psychiatry, University of Regensburg, Regenburg, Germany., Antila H; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Rog T; Department of Physics, University of Helsinki, Helsinki, Finland., Piepponen TP; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., Bramham CR; Department of Biomedicine and KG Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway., Normann C; 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., Lauri SE; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland., Saarma M; Institute of Biotechnology-HILIFE, University of Helsinki, Helsinki, Finland., Vattulainen I; Department of Physics, University of Helsinki, Helsinki, Finland; Computational Physics Laboratory, Tampere University, Tampere, Finland., Castrén E; Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland. Electronic address: eero.castren@helsinki.fi.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Mar 04; Vol. 184 (5), pp. 1299-1313.e19. Date of Electronic Publication: 2021 Feb 18.
DOI:	10.1016/j.cell.2021.01.034
Abstrakt:	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. Competing Interests: Declaration of interests E.C. and M.S. are shareholders of Herantis Pharma PIc that is not related to this study. E.C. has received lecture fees from Janssen-Cilag. Other authors declare no conflicts of interest. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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