Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis |
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Authors: | Kiyofumi Takahashi Hiroshi Miyoshi Masahiro Otomo Kenichi Osada Hideki Nakashima |
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Institution: | a Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan b Department of Microbiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan |
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Abstract: | Dynamin (Dyn) 1 plays a role in recycling of synaptic vesicles, and thus in nervous system function. We previously showed that sertraline, a selective serotonin reuptake inhibitor (SSRI), is a mixed-type inhibitor of Dyn 1 with respect to both GTP and l-α-phosphatidyl-l-serine (PS) in vitro, and we suggested that it may regulate the neurotransmitter transport by modulating synaptic vesicle endocytosis via inhibition of Dyn 1 GTPase. Here, we investigated the effect of sertraline on endocytosis of marker proteins in human neuroblastoma SH-Sy5Y cells and HeLa cells. Sertraline inhibited endocytosis in both cell lines. Western blotting showed that SH-Sy5Y expresses Dyn 1 and Dyn 2, while HeLa expresses only Dyn 2. GTPase assay showed that sertraline inhibited Dyn 2 as well as Dyn 1. Therefore, the effect of sertraline on endocytosis was mediated by Dyn 2, at least in HeLa cells, as well as by Dyn 1 in cell lines that express it. Moreover, the inhibition mechanism of transferrin (Tf) uptake by sertraline differed from that in cells expressing Dyn 1 K44A, a GTP binding-defective variant, and sertraline did not interfere with the interaction between Dyn 1 and PS-liposomes. |
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Keywords: | SSRI selective serotonin reuptake inhibitor His6 polyhistidine segment 6 residues in length Dyn dynamin Dyn-His6 dynamin 1 with a His6 tag fused to the C-terminus PHD pleckstrin homology domain PRD proline/arginine-rich domain SH3 Src homology 3 PS l-α-phosphatidyl-l-serine" target="_blank">l-α-phosphatidyl-l-serine Pi orthophosphate SPR surface plasmon resonance CTB cholera toxin subunit B Tf transferrin CPZ chlorpromazine DAPI 4&prime 6-diamidino-2-phenylindole CHC clathrin heavy chain |
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