Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

Show full item record



Permalink

http://hdl.handle.net/10138/329304

Citation

Casarotto , P C , Girych , M , Fred , S M , Kovaleva , V , Moliner , R , Enkavi , G , Biojone , C , Cannarozzo , C , Sahu , M P , Kaurinkoski , K , Brunello , C A , Steinzeig , A , Winkel , F , Patil , S , Vestring , S , Serchov , T , Diniz , C R A F , Laukkanen , L , Cardon , I , Antila , H , Rog , T , Piepponen , T P , Bramham , C R , Normann , C , Lauri , S E , Saarma , M , Vattulainen , I & Castren , E 2021 , ' Antidepressant drugs act by directly binding to TRKB neurotrophin receptors ' , Cell , vol. 184 , no. 5 , pp. 1299-+ . https://doi.org/10.1016/j.cell.2021.01.034

Title: Antidepressant drugs act by directly binding to TRKB neurotrophin receptors
Author: 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; Castren, Eero
Contributor organization: Neuroscience Center
Materials Physics
Institute of Biotechnology
Faculty of Pharmacy
Department of Physics
Divisions of Faculty of Pharmacy
Division of Pharmacology and Pharmacotherapy
Drug Research Program
Regenerative pharmacology group
Timo Petteri Piepponen / Principal Investigator
Molecular and Integrative Biosciences Research Programme
Syn­aptic Plas­ti­city and De­vel­op­ment
Mart Saarma / Principal Investigator
Date: 2021-03-04
Language: eng
Number of pages: 34
Belongs to series: Cell
ISSN: 0092-8674
DOI: https://doi.org/10.1016/j.cell.2021.01.034
URI: http://hdl.handle.net/10138/329304
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.
Subject: 1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
1_s2.0_S0092867421000775_main.pdf 7.755Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record