Truncations of amphiphysin I by calpain inhibit vesicle endocytosis during neural hyperexcitation.
Under normal physiological conditions, synaptic vesicle endocytosis is regulated by phosphorylation and Ca(2+)-dependent dephosphorylation of endocytic proteins such as amphiphysin and dynamin. To investigate the regulatory mechanisms that may occur under the conditions of excessive presynaptic Ca(2+) 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.
Wu
Yumei
Y
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho 2-5-1, Okayama 700-8558, Japan.
Liang
Shuang
S
Oda
Yoshiya
Y
Ohmori
Iori
I
Nishiki
Tei-ichi
T
Takei
Kohji
K
Matsui
Hideki
H
Tomizawa
Kazuhito
K
D000818:Animals; D002154:Calpain / Q000502:physiology*; D034284:Dynamin I / Q000378:metabolism; D004705:Endocytosis; D006624:Hippocampus / Q000378:metabolism; D006868:Hydrolysis; D008081:Liposomes; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D011188:Potassium / Q000378:metabolism
D008081:Liposomes; D009419:Nerve Tissue Proteins; C075637:amphiphysin; D002154:Calpain; D034284:Dynamin I; D011188:Potassium