Journal
CELL
Volume 184, Issue 5, Pages 1299-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.01.034
Keywords
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Funding
- ERC [322742]
- JPND CircProt [301225, 643417, 30122]
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Academy of Finland [294710, 307416, 297211]
- FAPESP [2018/18500-3, 2018/04250-5]
- Academy of Finland (Center of Excellence) [307415]
- Helsinki Institute of Life Science
- Human Frontier Science Program [RGP0059/2019]
- CSC-IT Center for Science
- German Research Council [SE 2666/2-1]
- Forschungskommission of the Medical Faculty of the University of Freiburg [SER1149/17]
- Academy of Finland (AKA) [297211, 297211] Funding Source: Academy of Finland (AKA)
- European Research Council (ERC) [322742] Funding Source: European Research Council (ERC)
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The study reveals that antidepressant drugs bind directly to the TRKB receptor, facilitating its activation at the synapse and potentially explaining the mechanism behind antidepressant action.
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.
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