title: Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis.
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-alpha-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.
authors.affiliation: Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Otomo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Osada
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
mesh_terms: D001798:Blood Proteins / Q000737:chemistry; D045744:Cell Line, Tumor; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034285:Dynamin II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D017434:Protein Structure, Tertiary / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*; D014168:Transferrin / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D034284:Dynamin I; D034285:Dynamin II; D010718:Phosphatidylserines; D010750:Phosphoproteins; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D014168:Transferrin; C039077:platelet protein P47