Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

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 antidepre...

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Bibliographic Details
Published in:Cell 2021-03, Vol.184 (5), p.1299-1313.e19
Main Authors: Casarotto, Plinio C., Girych, Mykhailo, Fred, Senem M., Kovaleva, Vera, Moliner, Rafael, Enkavi, Giray, Biojone, Caroline, Cannarozzo, Cecilia, Sahu, Madhusmita Pryiadrashini, Kaurinkoski, Katja, Brunello, Cecilia A., Steinzeig, Anna, Winkel, Frederike, Patil, Sudarshan, Vestring, Stefan, Serchov, Tsvetan, Diniz, Cassiano R.A.F., Laukkanen, Liina, Cardon, Iseline, Antila, Hanna, Rog, Tomasz, Piepponen, Timo Petteri, Bramham, Clive R., Normann, Claus, Lauri, Sari E., Saarma, Mart, Vattulainen, Ilpo, Castrén, Eero
Format: Article
Language:English
Subjects:
antidepressant
BDNF
cholesterol
fluoxetine
ketamine
Life Sciences
molecular dynamic simulation
neurotrophin
plasticity
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Summary: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. [Display omitted] •Several antidepressants, including SSRIs and ketamine, directly bind to TRKB•TRKB dimerization at transmembrane region forms a binding pocket for fluoxetine•Antidepressant binding to TRKB facilitates BDNF action and plasticity•Point mutation in TRKB transmembrane region blocks the effects of antidepressants Direct binding of both typical and fast-acting antidepressants to the BDNF receptor TRKB accounts for cell biological and behavioral actions of antidepressants. This mechanism directly connects antidepressant action to neuronal plasticity and may explain the slow action of typical antidepressants.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2021.01.034