Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2

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Fred , S M , Laukkanen , L , Brunello , C A , Vesa , L , Göös , H , Cardon , I , Moliner , R , Maritzen , T , Varjosalo , M , Casarotto , P C & Castren , E 2019 , ' Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2 ' , Journal of Biological Chemistry , vol. 294 , no. 48 , pp. 18150-18161 . https://doi.org/10.1074/jbc.RA119.008837

Title: Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2
Author: Fred, Senem Merve; Laukkanen, Liina; Brunello, Cecilia A.; Vesa, Liisa; Göös, Helka; Cardon, Iseline; Moliner, Rafael; Maritzen, Tanja; Varjosalo, Markku; Casarotto, Plinio C.; Castren, Eero
Contributor organization: Neuroscience Center
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Institute of Biotechnology
University Management
Molecular Systems Biology
Date: 2019-11-29
Language: eng
Number of pages: 12
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.RA119.008837
URI: http://hdl.handle.net/10138/313776
Abstract: Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB activation. Here, using MS, we found that a single intraperitoneal injection of fluoxetine disrupts the interaction of several proteins with TRKB in the hippocampus of mice. These proteins included members of adaptor protein complex-2 (AP-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking ? subunit of the AP-2 complex (AP2M) was confirmed to be disrupted by both acute and repeated fluoxetine treatments. Of note, fluoxetine disrupted the coupling between full-length TRKB and AP2M, but not the interaction between AP2M and the TRKB C-terminal region, indicating that the fluoxetine-binding site in TRKB lies outside the TRKB:AP2M interface. ELISA experiments revealed that in addition to fluoxetine, other chemically diverse antidepressants, such as imipramine, rolipram, phenelzine, ketamine, and its metabolite 2R,6R-hydroxynorketamine, also decreased the interaction between TRKB and AP2M in vitro. Silencing the expression of AP2M in a TRKB-expressing mouse fibroblast cell line (MG87.TRKB) increased cell-surface expression of TRKB and facilitated its activation by brain-derived neurotrophic factor (BDNF), observed as levels of phosphorylated TRKB. Moreover, animals haploinsufficient for the Ap2m1 gene displayed increased levels of active TRKB, along with enhanced cell-surface expression of the receptor in cultured hippocampal neurons. Taken together, our results suggest that disruption of the TRKB:AP2M interaction is a common mechanism underlying TRKB activation by several chemically diverse antidepressants.
Subject: brain-derived neurotrophic factor (BDNF)
clathrin
drug action
receptor tyrosine kinase
molecular pharmacology
neurotrophic receptor tyrosine kinase 2 (NTRK2)
adaptor protein complex-2 (AP-2)
neuroplasticity
NERVE GROWTH-FACTOR
NEUROTROPHIC FACTOR
RETROGRADE TRANSPORT
SURFACE EXPRESSION
SIGNALING PATHWAYS
PROTEOMIC ANALYSIS
PLASMA-MEMBRANE
AMPA RECEPTORS
CLATHRIN
TRAFFICKING
1182 Biochemistry, cell and molecular biology
3112 Neurosciences
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: acceptedVersion


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