| Autor: |
Schmitz, Sabine K, King, Cillian, Kortleven, Christian, Huson, Vincent, Kroon, Tim, Kevenaar, Josta T, Schut, Desiree, Saarloos, Ingrid, Hoetjes, Joost P, Wit, Heidi, Stiedl, Oliver, Spijker, Sabine, Li, Ka Wan, Mansvelder, Huibert D, Smit, August B, Cornelisse, Lennart Niels, Verhage, Matthijs, Toonen, Ruud F |
| Předmět: |
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| Zdroj: |
EMBO Journal; 6/1/2016, Vol. 35 Issue 11, p1236-1250, 15p |
| Abstrakt: |
Presynaptic cannabinoid ( CB1R) and metabotropic glutamate receptors ( mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase ( ERK) that mediates CB1R- and mGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission. ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventing ERK-dependent Munc18-1 phosphorylation increases synaptic strength. CB1R- and mGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation ( DSE) are reduced upon ERK/ MEK pathway inhibition and further reduced when ERK-dependent Munc18-1 phosphorylation is blocked. Thus, ERK-dependent Munc18-1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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