Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
Animals
Antidepressive Agents
/ chemistry
Binding Sites
Brain-Derived Neurotrophic Factor
/ metabolism
Cell Line
Cholesterol
/ metabolism
Embryo, Mammalian
Fluoxetine
/ chemistry
Hippocampus
/ metabolism
Humans
Mice
Models, Animal
Molecular Dynamics Simulation
Protein Domains
Rats
Receptor, trkB
/ chemistry
Visual Cortex
/ metabolism
BDNF
antidepressant
cholesterol
fluoxetine
ketamine
molecular dynamic simulation
neurotrophin
plasticity
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
04 03 2021
04 03 2021
Historique:
received:
26
02
2020
revised:
22
12
2020
accepted:
21
01
2021
pubmed:
20
2
2021
medline:
15
9
2021
entrez:
19
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33606976
pii: S0092-8674(21)00077-5
doi: 10.1016/j.cell.2021.01.034
pmc: PMC7938888
pii:
doi:
Substances chimiques
Antidepressive Agents
0
Brain-Derived Neurotrophic Factor
0
Fluoxetine
01K63SUP8D
Cholesterol
97C5T2UQ7J
Receptor, trkB
EC 2.7.10.1
Banques de données
figshare
['10.6084/m9.figshare.12698012']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1299-1313.e19Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
Références
Biol Psychiatry. 2006 Jun 15;59(12):1116-27
pubmed: 16631126
Nat Rev Neurosci. 2013 Jan;14(1):7-23
pubmed: 23254191
J Affect Disord. 2019 Oct 1;257:55-63
pubmed: 31299405
Front Synaptic Neurosci. 2013 Oct 18;5:9
pubmed: 24151466
Lancet. 2018 Nov 24;392(10161):2299-2312
pubmed: 30396512
Nat Commun. 2016 Nov 22;7:13535
pubmed: 27874004
Methods Mol Biol. 2014;1195:133-44
pubmed: 24504930
J Neurosci. 2005 Feb 2;25(5):1089-94
pubmed: 15689544
Cleve Clin J Med. 2019 Dec;86(12):807-814
pubmed: 31821138
J Neurosci. 2000 Dec 15;20(24):9104-10
pubmed: 11124987
Biol Psychiatry. 2008 Feb 15;63(4):349-52
pubmed: 17643398
Nat Commun. 2014 Sep 10;5:4863
pubmed: 25204588
EMBO Mol Med. 2014 May 30;6(7):902-17
pubmed: 24878762
Nat Rev Neurosci. 2009 Dec;10(12):850-60
pubmed: 19927149
J Neurosci. 2007 Jun 13;27(24):6417-27
pubmed: 17567802
Behav Brain Res. 2013 Jun 15;247:92-100
pubmed: 23511254
Science. 2001 Nov 9;294(5545):1354-7
pubmed: 11701931
PLoS Comput Biol. 2015 Sep 01;11(9):e1004398
pubmed: 26325167
Nat Rev Mol Cell Biol. 2008 Feb;9(2):125-38
pubmed: 18216769
Annu Rev Med. 2015;66:509-23
pubmed: 25341010
Biol Psychiatry. 2009 Jul 1;66(1):5-8
pubmed: 19251245
J Comput Aided Mol Des. 2015 May;29(5):397-411
pubmed: 25808134
Nat Methods. 2006 Dec;3(12):977-9
pubmed: 17099704
PLoS One. 2017 Aug 16;12(8):e0181788
pubmed: 28813435
Curr Opin Struct Biol. 2004 Aug;14(4):465-79
pubmed: 15313242
Arch Gen Psychiatry. 2006 Aug;63(8):856-64
pubmed: 16894061
J Biol Chem. 2016 Sep 16;291(38):19725-19733
pubmed: 27432886
Bioinformatics. 2006 Mar 1;22(5):623-5
pubmed: 16397007
Neuron. 2005 Dec 8;48(5):797-809
pubmed: 16337917
J Affect Disord. 2004 Aug;81(2):161-6
pubmed: 15306143
Methods Enzymol. 2012;504:127-46
pubmed: 22264532
J Cell Biol. 2000 Mar 6;148(5):997-1008
pubmed: 10704449
Cell Physiol Biochem. 2010;26(1):9-20
pubmed: 20502000
N Engl J Med. 2008 Jan 3;358(1):55-68
pubmed: 18172175
PLoS One. 2011;6(6):e20161
pubmed: 21731610
Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
pubmed: 9895674
Prog Lipid Res. 2011 Oct;50(4):357-71
pubmed: 21741992
Neuron. 2003 May 22;38(4):529-45
pubmed: 12765606
Science. 2008 Apr 18;320(5874):385-8
pubmed: 18420937
J Neurosci. 2007 May 2;27(18):4859-69
pubmed: 17475794
J Neurosci Methods. 2014 Jan 30;222:142-6
pubmed: 24239780
Neuron. 1997 Sep;19(3):653-64
pubmed: 9331355
J Comput Chem. 2017 Jun 5;38(15):1114-1124
pubmed: 27862047
J Cell Biol. 2004 Dec 20;167(6):1205-15
pubmed: 15596541
Neuropsychopharmacology. 2000 Oct;23(4):428-38
pubmed: 10989270
J Neurosci. 2021 Feb 3;41(5):972-980
pubmed: 33293360
J Anal Toxicol. 2007 Sep;31(7):409-14
pubmed: 17725889
BMC Bioinformatics. 2010 Jan 13;11:25
pubmed: 20070892
J Biol Chem. 2002 Nov 8;277(45):43160-7
pubmed: 12202482
Nature. 2010 Sep 2;467(7311):59-63
pubmed: 20811452
Oncogene. 1999 Feb 11;18(6):1285-96
pubmed: 10022810
JAMA Psychiatry. 2013 Sep;70(9):983-9
pubmed: 23842648
Cell. 2017 Feb 23;168(5):878-889.e29
pubmed: 28235199
PLoS One. 2012;7(3):e32869
pubmed: 22396798
Bioinformatics. 2018 Mar 15;34(6):1061-1062
pubmed: 29126305
J Neurophysiol. 1998 Jan;79(1):496-9
pubmed: 9425220
Neurosci Biobehav Rev. 2007;31(5):673-704
pubmed: 17368764
Biophys J. 2006 Oct 15;91(8):2798-814
pubmed: 16844742
J Neuropsychiatry Clin Neurosci. 1993 Summer;5(3):322-9
pubmed: 8369643
Neuropharmacology. 2014 Jan;76 Pt C:664-76
pubmed: 23831365
J Am Chem Soc. 2011 Oct 5;133(39):15487-95
pubmed: 21861483
J Cell Biol. 2000 Sep 18;150(6):1423-34
pubmed: 10995446
Pharmacol Rev. 2018 Jul;70(3):621-660
pubmed: 29945898
Cell. 2013 Jan 31;152(3):543-56
pubmed: 23374349
Nature. 2016 May 04;533(7604):481-6
pubmed: 27144355
Neuropharmacology. 2018 Jun;135:163-171
pubmed: 29550391
Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1150-5
pubmed: 24395770
Chem Biol. 2009 Jun 26;16(6):644-56
pubmed: 19549602
Mol Biol Cell. 2016 Nov 7;27(22):3480-3489
pubmed: 27535429
Adv Exp Med Biol. 2019;1135:3-25
pubmed: 31098808
Science. 2015 Apr 10;348(6231):239-42
pubmed: 25859045
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10827-32
pubmed: 15249684
Nucleic Acids Res. 2017 Jan 4;45(D1):D250-D255
pubmed: 27510400
Neuron. 1998 Oct;21(4):681-93
pubmed: 9808456
Neuropsychopharmacology. 2007 Oct;32(10):2152-62
pubmed: 17314919
Cell Rep. 2016 Jan 12;14(2):255-68
pubmed: 26748707
Neuronal Signal. 2019 Apr 26;3(2):NS20180207
pubmed: 32714598
J Biol Chem. 2008 May 9;283(19):13280-8
pubmed: 18353779
PLoS One. 2012;7(4):e34024
pubmed: 22529904
J Affect Disord. 2019 Mar 1;246:706-715
pubmed: 30611914
J Neurosci. 2002 Sep 1;22(17):7453-61
pubmed: 12196567
Psychopharmacology (Berl). 2011 May;215(2):231-7
pubmed: 21181120
J Chem Theory Comput. 2010 Jul 1;6(9):2559-2565
pubmed: 21857813
Biol Psychiatry. 2000 Feb 15;47(4):351-4
pubmed: 10686270
Nat Rev Drug Discov. 2013 Jul;12(7):507-25
pubmed: 23977697
Neuropsychopharmacology. 2016 Jun;41(7):1733-41
pubmed: 26514584
PLoS One. 2011;6(6):e20567
pubmed: 21666748
J Neural Transm Suppl. 1995;46:315-23
pubmed: 8821068
Biol Psychiatry. 2018 Jul 1;84(1):55-64
pubmed: 29174591
Methods Enzymol. 2012;505:47-58
pubmed: 22289447
Neuron. 2001 Oct 11;32(1):123-40
pubmed: 11604144
J Phys Chem B. 2010 Jun 17;114(23):7830-43
pubmed: 20496934
Neuromolecular Med. 2016 Mar;18(1):109-33
pubmed: 26707855
Mol Psychiatry. 2017 Aug;22(8):1085-1095
pubmed: 28397840
Nat Cell Biol. 2007 Jan;9(1):7-14
pubmed: 17199125
J Chem Phys. 2008 Sep 28;129(12):124105
pubmed: 19045004
Pharmacol Rev. 2012 Apr;64(2):238-58
pubmed: 22407616
Cell. 2013 Jan 31;152(3):557-69
pubmed: 23374350
Science. 2003 Aug 8;301(5634):805-9
pubmed: 12907793
Lancet Psychiatry. 2017 May;4(5):409-418
pubmed: 28153641
J Biol Chem. 2019 Nov 29;294(48):18150-18161
pubmed: 31631060
Biosci Rep. 2020 Jan 31;40(1):
pubmed: 31850494
J Cell Biol. 2013 Nov 11;203(3):385-93
pubmed: 24217616
Front Cell Neurosci. 2019 Jun 06;13:231
pubmed: 31244606
EMBO J. 2016 Dec 15;35(24):2699-2716
pubmed: 27879284
Genes Brain Behav. 2012 Jul;11(5):503-12
pubmed: 22530815
Mol Psychiatry. 2019 Dec;24(12):1833-1843
pubmed: 29895894
J Pharm Biomed Anal. 1998 Oct;18(1-2):193-9
pubmed: 9863958
J Neurosci. 2003 Jan 1;23(1):349-57
pubmed: 12514234
Front Physiol. 2013 Feb 28;4:31
pubmed: 23450735
J Chem Inf Model. 2012 Dec 21;52(12):3155-68
pubmed: 23145473
Cell Mol Neurobiol. 2005 Sep;25(6):973-80
pubmed: 16392030
Nat Methods. 2017 Jan;14(1):71-73
pubmed: 27819658
Am J Psychiatry. 2000 Sep;157(9):1506-8
pubmed: 10964871
Science. 2011 Dec 23;334(6063):1731-4
pubmed: 22194582
J Vis Exp. 2011 Apr 16;(50):
pubmed: 21525845
Trends Neurosci. 2003 Apr;26(4):171-3
pubmed: 12689763
Cell Chem Biol. 2018 Jul 19;25(7):857-870.e7
pubmed: 29731426
Neuron. 2002 Sep 26;36(1):121-37
pubmed: 12367511
Biochim Biophys Acta. 2012 Feb;1818(2):183-93
pubmed: 21910966
Neuropharmacology. 2017 Nov;126:250-256
pubmed: 28887184