Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

Plinio  Casarotto; Mykhailo Girych; Senem Merve Fred; Vera Kovaleva; Rafael Moliner; Giray Enkavi; Caroline Biojone; Cecilia Cannarozzo; Madhusmita  Pryiadrashini Sahu; Katja Kaurinkoski; Cecilia A. Brunello; Anna Steinzeig; Frederike  Winkel; Sudarshan  Patil; Stefan Vestring; Tsvetan Serchov; Cassiano Ricardo Alves Faria Diniz; Liina Laukkanen; Iseline  Cardon; Hanna  Antila; Tomasz Róg; Timo Petteri Piepponen; Clive R Bramham; Claus  Normann; Sari  E Lauri; Mart Saarma; Ilpo Vattulainen; Eero Castren

Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

Plinio Casarotto, Mykhailo Girych, Senem Merve Fred, Vera Kovaleva, Rafael Moliner, Giray Enkavi, Caroline Biojone, Cecilia Cannarozzo, Madhusmita Pryiadrashini Sahu, Katja Kaurinkoski, Cecilia A. Brunello, Anna Steinzeig, Frederike Winkel, Sudarshan Patil, Stefan Vestring, Tsvetan Serchov, Cassiano Ricardo Alves Faria Diniz, Liina Laukkanen, Iseline Cardon, Hanna AntilaTomasz Róg, Timo Petteri Piepponen, Clive R Bramham, Claus Normann, Sari E Lauri, Mart Saarma, Ilpo Vattulainen, Eero Castren^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

426 Citations (Scopus)

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. 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.

Original language	English
Journal	Cell
Pages (from-to)	1299-1313.e19
ISSN	0092-8674
Publication status	Published - 4 Mar 2021
Externally published	Yes

Keywords

BDNF
antidepressant
cholesterol
fluoxetine
ketamine
molecular dynamic simulation
neurotrophin
plasticity

Cite this

Casarotto, P., Girych, M., Fred, S. M., Kovaleva, V., Moliner, R., Enkavi, G., Biojone, C., Cannarozzo, C., Pryiadrashini Sahu, M., Kaurinkoski, K., Brunello, C. A., Steinzeig, A., Winkel, F., Patil, S., Vestring, S., Serchov, T., Diniz, C. R. A. F., Laukkanen, L., Cardon, I., ... Castren, E. (2021). Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell, 1299-1313.e19.

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title = "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors",

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. 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.",

keywords = "BDNF, antidepressant, cholesterol, fluoxetine, ketamine, molecular dynamic simulation, neurotrophin, plasticity",

author = "Plinio Casarotto and Mykhailo Girych and Fred, {Senem Merve} and Vera Kovaleva and Rafael Moliner and Giray Enkavi and Caroline Biojone and Cecilia Cannarozzo and {Pryiadrashini Sahu}, Madhusmita and Katja Kaurinkoski and Brunello, {Cecilia A.} and Anna Steinzeig and Frederike Winkel and Sudarshan Patil and Stefan Vestring and Tsvetan Serchov and Diniz, {Cassiano Ricardo Alves Faria} and Liina Laukkanen and Iseline Cardon and Hanna Antila and Tomasz R{\'o}g and {Petteri Piepponen}, Timo and Bramham, {Clive R} and Claus Normann and {E Lauri}, Sari and Mart Saarma and Ilpo Vattulainen and Eero Castren",

year = "2021",

month = mar,

day = "4",

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pages = "1299--1313.e19",

journal = "Cell",

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Casarotto, P, Girych, M, Fred, SM, Kovaleva, V, Moliner, R, Enkavi, G, Biojone, C, Cannarozzo, C, Pryiadrashini Sahu, M, Kaurinkoski, K, Brunello, CA, Steinzeig, A, Winkel, F, Patil, S, Vestring, S, Serchov, T, Diniz, CRAF, Laukkanen, L, Cardon, I, Antila, H, Róg, T, Petteri Piepponen, T, Bramham, CR, Normann, C, E Lauri, S, Saarma, M, Vattulainen, I & Castren, E 2021, 'Antidepressant drugs act by directly binding to TRKB neurotrophin receptors', Cell, pp. 1299-1313.e19.

TY - JOUR

T1 - Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

AU - Casarotto, Plinio

AU - Girych, Mykhailo

AU - Fred, Senem Merve

AU - Kovaleva, Vera

AU - Moliner, Rafael

AU - Enkavi, Giray

AU - Biojone, Caroline

AU - Cannarozzo, Cecilia

AU - Pryiadrashini Sahu, Madhusmita

AU - Kaurinkoski, Katja

AU - Brunello, Cecilia A.

AU - Steinzeig, Anna

AU - Winkel, Frederike

AU - Patil, Sudarshan

AU - Vestring, Stefan

AU - Serchov, Tsvetan

AU - Diniz, Cassiano Ricardo Alves Faria

AU - Laukkanen, Liina

AU - Cardon, Iseline

AU - Antila, Hanna

AU - Róg, Tomasz

AU - Petteri Piepponen, Timo

AU - Bramham, Clive R

AU - Normann, Claus

AU - E Lauri, Sari

AU - Saarma, Mart

AU - Vattulainen, Ilpo

AU - Castren, Eero

PY - 2021/3/4

Y1 - 2021/3/4

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 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. 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.

AB - 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. 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.

KW - BDNF

KW - antidepressant

KW - cholesterol

KW - fluoxetine

KW - ketamine

KW - molecular dynamic simulation

KW - neurotrophin

KW - plasticity

UR - http://www.scopus.com/inward/record.url?scp=85101671832&partnerID=8YFLogxK

M3 - Journal article

SN - 0092-8674

SP - 1299-1313.e19

JO - Cell

JF - Cell

ER -

Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

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