PMID- 31631060
OWN - NLM
STAT- MEDLINE
DCOM- 20200609
LR  - 20231020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 48
DP  - 2019 Nov 29
TI  - Pharmacologically diverse antidepressants facilitate TRKB receptor activation by 
      disrupting its interaction with the endocytic adaptor complex AP-2.
PG  - 18150-18161
LID - S0021-9258(20)30681-5 [pii]
LID - 10.1074/jbc.RA119.008837 [doi]
AB  - 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 mu 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.
CI  - (c) 2019 Fred et al.
FAU - Fred, Senem Merve
AU  - Fred SM
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
FAU - Laukkanen, Liina
AU  - Laukkanen L
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
FAU - Brunello, Cecilia A
AU  - Brunello CA
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
FAU - Vesa, Liisa
AU  - Vesa L
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
FAU - Goos, Helka
AU  - Goos H
AD  - Institute of Biotechnology-HiLIFE, University of Helsinki, 00014 Helsinki, 
      Finland.
FAU - Cardon, Iseline
AU  - Cardon I
AD  - Brain Master Program, Faculty of Science, Aix-Marseille Universite, 13007 
      Marseille, France.
FAU - Moliner, Rafael
AU  - Moliner R
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
FAU - Maritzen, Tanja
AU  - Maritzen T
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), 13125 Berlin, 
      Germany.
FAU - Varjosalo, Markku
AU  - Varjosalo M
AD  - Institute of Biotechnology-HiLIFE, University of Helsinki, 00014 Helsinki, 
      Finland.
FAU - Casarotto, Plinio C
AU  - Casarotto PC
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland. 
      Electronic address: plinio.casarotto@helsinki.fi.
FAU - Castren, Eero
AU  - Castren E
AD  - Neuroscience Center-HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191020
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Protein Complex 2)
RN  - 0 (Antidepressive Agents)
RN  - 0 (Membrane Glycoproteins)
RN  - EC 2.7.10.1 (Ntrk2 protein, mouse)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
SB  - IM
MH  - Adaptor Protein Complex 2/*metabolism
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Cell Line
MH  - Endocytosis/*drug effects
MH  - Enzyme Activation/drug effects
MH  - Fibroblasts/metabolism
MH  - Hippocampus/*metabolism
MH  - Male
MH  - Membrane Glycoproteins/*metabolism
MH  - Mice
MH  - Neurons/*metabolism
MH  - Protein-Tyrosine Kinases/*metabolism
PMC - PMC6885648
OTO - NOTNLM
OT  - adaptor protein complex-2 (AP-2)
OT  - brain-derived neurotrophic factor (BDNF)
OT  - clathrin
OT  - drug action
OT  - molecular pharmacology
OT  - neuroplasticity
OT  - neurotrophic receptor tyrosine kinase 2 (NTRK2)
OT  - receptor tyrosine kinase
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2019/10/22 06:00
MHDA- 2020/06/10 06:00
PMCR- 2020/11/29
CRDT- 2019/10/22 06:00
PHST- 2019/04/10 00:00 [received]
PHST- 2019/10/15 00:00 [revised]
PHST- 2019/10/22 06:00 [pubmed]
PHST- 2020/06/10 06:00 [medline]
PHST- 2019/10/22 06:00 [entrez]
PHST- 2020/11/29 00:00 [pmc-release]
AID - S0021-9258(20)30681-5 [pii]
AID - RA119.008837 [pii]
AID - 10.1074/jbc.RA119.008837 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Nov 29;294(48):18150-18161. doi: 10.1074/jbc.RA119.008837. Epub 
      2019 Oct 20.