Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1

Sabine K Schmitz, Cillian King, Christian Kortleven, Vincent Huson, Tim Kroon, Josta T Kevenaar, Desiree Schut, Ingrid Saarloos, Joost P Hoetjes, Heidi de Wit, Oliver Stiedl, Sabine Spijker, Ka Wan Li, Huibert D Mansvelder, August B Smit, Lennart Niels Cornelisse, Matthijs Verhage, Ruud F Toonen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1236-50
Number of pages15
JournalEMBO Journal
Volume35
Issue number11
DOIs
Publication statusPublished - 1 Jun 2016

Cite this

Schmitz, S. K., King, C., Kortleven, C., Huson, V., Kroon, T., Kevenaar, J. T., ... Toonen, R. F. (2016). Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1. EMBO Journal, 35(11), 1236-50. https://doi.org/10.15252/embj.201592244