Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

Author(s):Show less -

Casarotto, Plinio C. ^[1] ; Girych, Mykhailo ^[2] ; Fred, Senem M. ^[1] ; Kovaleva, Vera ^[3] ; Moliner, Rafael ^[1] ; Enkavi, Giray ^[2] ; Biojone, Caroline ^[1] ; Cannarozzo, Cecilia ^[1] ; Sahu, Madhusmita Pryiadrashini ^[1] ; Kaurinkoski, Katja ^[1] ; Brunello, Cecilia A. ^[1] ; Steinzeig, Anna ^[1] ; Winkel, Frederike ^[1] ; Patil, Sudarshan ^{[4, 5]} ; Vestring, Stefan ^{[6, 7]} ; Serchov, Tsvetan ^{[6, 8]} ; Diniz, Cassiano R. A. F. ^{[9, 1]} ; Laukkanen, Liina ^[1] ; Cardon, Iseline ^{[1, 10, 11]} ; Antila, Hanna ^{[1, 12]} ; Rog, Tomasz ^[2] ; Piepponen, Timo Petteri ^[13] ; Bramham, Clive R. ^{[4, 5]} ; Normann, Claus ^{[6, 14]} ; Lauri, Sari E. ^{[1, 15]} ; Saarma, Mart ^[3] ; Vattulainen, Ilpo ^{[2, 16]} ; Castren, Eero ^[1]

Affiliation:Show less -

^[1] Univ Helsinki, Neurosci Ctr, HILIFE, Helsinki - Finland

^[2] Univ Helsinki, Dept Phys, Helsinki - Finland

^[3] Univ Helsinki, Inst Biotechnol, HILIFE, Helsinki - Finland

^[4] Univ Bergen, Dept Biomed, Bergen - Norway

^[5] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen - Norway

^[6] Univ Freiburg, Med Ctr Univ Freiburg, Fac Med, Dept Psychiat & Psychotherapy, Freiburg - Germany

^[7] Univ Freiburg, Fac Med, Berta Ottenstein Programme Clinician Scientists, Freiburg - Germany

^[8] Univ Strasbourg, Ctr Natl Rech Sci CNRS, Inst Neurosci Cellulaires & Integrat, F-67000 Strasbourg - France

^[9] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Sao Paulo - Brazil

^[10] Aix Marseille Univ, Fac Sci, Brain Master Program, Marseille - France

^[11] Univ Regensburg, Dept Psychiat, Regenburg - Germany

^[12] Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 - USA

^[13] Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Helsinki - Finland

^[14] Univ Freiburg, Ctr Basics Neuromodulat NeuroModul Basics, Freiburg - Germany

^[15] Univ Helsinki, Mol & Integrat Biosci Res Program, Helsinki - Finland

^[16] Tampere Univ, Computat Phys Lab, Tampere - Finland

• Document type: Journal article
• Source: Cell; v. 184, n. 5, p. 1299+, MAR 4 2021.
• Web of Science Citations: 3

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. (AU)

• FAPESP's process: 18/04250-5 - Study of the relevance of p75 receptor activation for the effect of antidepressants on the extinction memory
• Grantee: Cassiano Ricardo Alves Faria Diniz
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/18500-3 - Study of the relevance of p75 receptor activation for the effect of fluoxetine on the extinction memory
• Grantee: Cassiano Ricardo Alves Faria Diniz
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor