期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 9, 页码 3157-3166出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3712-09.2010
关键词
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资金
- National Institutes of Health [DA 026922]
- UCLA Udall Parkinson Disease Center of Excellence [NS038367]
- American Parkinson Disease Association
The ubiquitin proteasome system (UPS) plays a crucial role in modulating synaptic physiology both presynaptically and postsynaptically, but the regulatory mechanisms remain obscure. To determine acute effects of proteasome inhibition on neurotransmission, we performed whole-cell voltage-clamp recordings from cultured rodent hippocampal neurons. We find that proteasome inhibitors induce a strikingly fast, severalfold increase in the frequency of both miniature (mini) and spontaneous synaptic currents at excitatory and inhibitory synapses. The lack of change in mini amplitude and kinetics indicates a presynaptic site of action. This effect does not depend on increased levels of presynaptic proteins, previously suggested as proteasomal targets. Furthermore, blockade of the UPS using E1-activating enzyme inhibitors also increases mini frequency, demonstrating that accumulation of ubiquitinated proteins is not required. Overall, these data suggest that the UPS not only orchestrates protein turnover, but also dynamically regulates the activity state of presynaptic proteins, thus crucially shaping synaptic transmission.
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