Some Selective Serotonin Reuptake Inhibitors Inhibit Dynamin I Guanosine Triphosphatase (GTPase)

• Published in: Biological & Pharmaceutical Bulletin Vol. 31; no. 8; pp. 1489 - 1495
• Main Authors: Otomo, Masahiro, Takahashi, Kiyofumi, Miyoshi, Hiroshi, Osada, Kenichi, Nakashima, Hideki, Yamaguchi, Noboru
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-08-2008; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; dynamin; Dynamin I - antagonists & inhibitors; Dynamin I - genetics; endocytosis; Endocytosis - drug effects; Enzyme Inhibitors - pharmacology; Escherichia coli - genetics; Fluvoxamine - pharmacology; Genetic Vectors; guanosine triphosphatase; inhibitor; Kinetics; Mice; Plasmids - genetics; Psychotropic Drugs - pharmacology; selective serotonin reuptake inhibitor; Serotonin Uptake Inhibitors; Sertraline - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.31.1489

Neuronal dynamin I plays a critical role in the recycling of synaptic vesicles, and thus in nervous system function. We expressed and purified dynamin I to explore potentially clinically useful endocytosis inhibitors and to examine the mechanism of their action. We estimated the IC50 of nineteen psychotropic drugs for dynamin I. The IC50 values of two selective serotonin reuptake inhibitors (sertraline and fluvoxamine) were 7.3±1.0 and 14.7±1.6 μM, respectively. Kinetic analyses revealed that fluvoxamine is a noncompetitive inhibitor of dynamin I guanosine triphosphatase (GTPase) with respect to guanosine 5′-triphosphate (GTP) and a competitive inhibitor with respect to L-phosphatidylserine (PS). Fluvoxamine may compete with PS for binding to the pleckstrin homology domain of dynamin I. On the other hand, sertraline was a mixed type inhibitor with respect to both GTP and PS. Our results indicate that sertraline and fluvoxamine may regulate the transportation of neurotransmitters by modulating synaptic vesicle endocytosis via the inhibition of dynamin I GTPase.