Presynaptic inhibition upon CB 1 or mG lu2/3 receptor activation requires ERK / MAPK phosphorylation of Munc18‐1

• DOI: 10.15252/embj.201592244
• Publication Date: 2016-04-08T13:23:39Z
• Authors: 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 Cor...; Matthijs Verhage; Ruud F Toonen
• Keywords: Male; Mice, Knockout; Neurons; 0301 basic medicine; Excitatory Postsynaptic Potentials; In Vitro Techniques; Embryo, Mammalian; Receptors, Metabotropic Glutamate; Hippocampus; Electric Stimulation; Mice, Inbred C57BL; 03 medical and health sciences; HEK293 Cells; Munc18 Proteins; Receptor, Cannabinoid, CB1; Pregnancy; Animals; Humans; Female; Mitogen-Activated Protein Kinases; Phosphorylation; Rats, Wistar

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.