PT  - JOURNAL ARTICLE
AU  - Gina V. Rinetti
AU  - Felix E. Schweizer
TI  - Ubiquitination Acutely Regulates Presynaptic Neurotransmitter Release in Mammalian Neurons
AID  - 10.1523/JNEUROSCI.3712-09.2010
DP  - 2010 Mar 03
TA  - The Journal of Neuroscience
PG  - 3157--3166
VI  - 30
IP  - 9
4099  - http://www.jneurosci.org/content/30/9/3157.short
4100  - http://www.jneurosci.org/content/30/9/3157.full
SO  - J. Neurosci.2010 Mar 03; 30
AB  - 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.