Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2
| Autor: | Iseline Cardon, Liisa Vesa, Plinio C. Casarotto, Rafael Moliner, Tanja Maritzen, Senem Merve Fred, Cecilia A. Brunello, Markku Varjosalo, Eero Castrén, Liina Laukkanen, Helka Göös |
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| Přispěvatelé: | Neuroscience Center, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Institute of Biotechnology, University Management, Molecular Systems Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Tropomyosin receptor kinase B SURFACE EXPRESSION Biochemistry Hippocampus Receptor tyrosine kinase Mice Neurobiology Neurotrophic factors drug action RETROGRADE TRANSPORT Receptor Neurons Membrane Glycoproteins biology Chemistry musculoskeletal neural and ocular physiology Signal transducing adaptor protein neurotrophic receptor tyrosine kinase 2 (NTRK2) Protein-Tyrosine Kinases Antidepressive Agents Endocytosis 3. Good health Cell biology CLATHRIN embryonic structures PROTEOMIC ANALYSIS Signal transduction medicine.drug neuroplasticity Adaptor Protein Complex 2 AMPA receptor Cell Line SIGNALING PATHWAYS 03 medical and health sciences medicine Animals TRAFFICKING brain-derived neurotrophic factor (BDNF) Molecular Biology Rolipram 030102 biochemistry & molecular biology AMPA RECEPTORS NERVE GROWTH-FACTOR 3112 Neurosciences molecular pharmacology Cell Biology Fibroblasts Enzyme Activation 030104 developmental biology nervous system PLASMA-MEMBRANE biology.protein receptor tyrosine kinase 1182 Biochemistry cell and molecular biology adaptor protein complex-2 (AP-2) NEUROTROPHIC FACTOR |
| Zdroj: | J Biol Chem |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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