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PNAS 100 (25): 14908-14913

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Rapid Ca2+-dependent decrease of protein ubiquitination at synapses

Hong Chen{dagger}, Simona Polo{ddagger}, Pier Paolo Di Fiore{ddagger},§, and Pietro V. De Camilli{dagger},¶

{dagger}Howard Hughes Medical Institute and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510; {ddagger}European Institute of Oncology, 20141 Milan, Italy; and §The Italian Foundation of Cancer Research Institute for Molecular Oncology and University of Milano School of Medicine, 20139 Milan, Italy

Contributed by Pietro V. De Camilli, October 13, 2003

Abstract: Protein ubiquitination has been implicated in the regulation of axonal growth and synaptic plasticity as well as in the pathogenesis of neurodegenerative diseases. Here we show that depolarization-dependent Ca2+ influx into synaptosomes produces a global, rapid (range of seconds), and reversible decrease of the ubiquitinated state of proteins, which correlates with the Ca2+-dependent dephosphorylation of several synaptic proteins. A similar general decrease in protein ubiquitination was observed in nonneuronal cells on Ca2+ entry induced by ionomycin. Both in synaptosomes and in nonneuronal cells, this decrease was blocked by FK506 (a calcineurin antagonist). Proteins whose ubiquitinated state was decreased include epsin 1, a substrate for the deubiquitinating enzyme fat facets/FAM, which we show here to be concentrated at synapses. These results reveal a fast regulated turnover of protein ubiquitination. In nerve terminals, protein ubiquitination may play a role both in the regulation of synaptic function, including vesicle traffic, and in the coordination of protein turnover with synaptic use.

To whom correspondence should be addressed. E-mail: pietro.decamilli{at}yale.edu.

Abbreviations: HA, hemagglutinin; DMEM*, serum-free DMEM supplemented with 1 mM CaCl2; siRNA, small interfering RNA; CHO, Chinese hamster ovary.

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