TY - JOUR T1 - Antidepressant drugs act by directly binding to TRKB neurotrophin receptors JF - bioRxiv DO - 10.1101/757989 SP - 757989 AU - Plinio C Casarotto AU - Mykhailo Girych AU - Senem M Fred AU - Vera Kovaleva AU - Rafael Moliner AU - Giray Enkavi AU - Caroline Biojone AU - Cecilia Cannarozzo AU - Madhusmita Pryiadrashini Sahu AU - Katja Kaurinkoski AU - Cecilia A Brunello AU - Anna Steinzeig AU - Frederike Winkel AU - Sudarshan Patil AU - Stefan Vestring AU - Tsvetan Serchov AU - Cassiano RAF Diniz AU - Liina Laukkanen AU - Iseline Cardon AU - Hanna Antila AU - Tomasz Rog AU - Timo Petteri Piepponen AU - Clive R Bramham AU - Claus Normann AU - Sari E Lauri AU - Mart Saarma AU - Ilpo Vattulainen AU - Eero Castrén Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/15/757989.abstract N2 - 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 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 the allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which proposes a framework for how molecular effects of antidepressants are translated into clinical mood recovery.Competing Interest StatementEC and MS are shareholders of Herantis Pharma PIc that is not related to this study; EC has received lecture fees from Janssen-Cilag. Other authors declare no conflict of interest. ER -