Article
- The EMBO Journal (2007) 26, 2981 - 2990
- doi:10.1038/sj.emboj.7601741
Published online: 31 May 2007
Subject Category:
Truncations of amphiphysin I by calpain inhibit vesicle endocytosis during neural hyperexcitation
Yumei Wu1, Shuang Liang2, Yoshiya Oda3, Iori Ohmori1, Tei-ichi Nishiki1, Kohji Takei2, Hideki Matsui1 and Kazuhito Tomizawa1
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Department of Neuroscience, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Laboratory of Seed Finding Technology, Eisai Co., Ltd, Tsukuba, Japan
Correspondence to:
Kazuhito Tomizawa, Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho 2-5-1, Okayama 700-8558, Japan. Tel.: +81 86 235 7107; Fax: +81 86 235 7111; E-mail: tomikt@md.okayama-u.ac.jp
Received 19 April 2007; Accepted 8 May 2007
Abstract
Under normal physiological conditions, synaptic vesicle endocytosis is regulated by phosphorylation and Ca2+-dependent dephosphorylation of endocytic proteins such as amphiphysin and dynamin. To investigate the regulatory mechanisms that may occur under the conditions of excessive presynaptic Ca2+ influx observed preceding neural hyperexcitation, we examined hippocampal slices following high-potassium or high-frequency electrical stimulation (HFS). In both cases, three truncated forms of amphiphysin I resulted from cleavage by the protease calpain. In vitro, the binding of truncated amphiphysin I to dynamin I and copolymerization into rings with dynamin I were inhibited, but its interaction with liposomes was not affected. Moreover, overexpression of the truncated form of amphiphysin I inhibited endocytosis of transferrin and synaptic vesicles. Inhibiting calpain prevented HFS-induced depression of presynaptic transmission. Finally, calpain-dependent amphiphysin I cleavage attenuated kainate-induced seizures. These results suggest that calpain-dependent cleavage of amphiphysin I inhibits synaptic vesicle endocytosis during neural hyperexcitation and demonstrate a novel post-translational regulation of endocytosis.
Keywords:
- amphiphysin,
- calpain,
- endocytosis,
- hyperexcitation,
- seizure
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