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.
ERK‐dependent Munc18‐1 phosphorylation contributes to synaptic depression upon activation of presynaptic CB1 or mGlu2/3 receptors and during intense neuronal activity.
Munc18‐1 is a presynaptic ERK substrate in vivo.
ERK produces synaptic depression by phosphorylating Munc18‐1.
ERK‐dependent Munc18‐1 phosphorylation is a major factor in CB1R‐ and mGluR2/3‐induced presynaptic inhibition and depolarization suppression of excitation (DSE).
- Received June 8, 2015.
- Revision received February 28, 2016.
- Accepted March 2, 2016.
- © 2016 The Authors
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