Reference : Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phos...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Multidisciplinary, general & others
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/26826

Title :	Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.
Language :	English
Author, co-author :	Schmitz, Sabine [Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands > Department of Functional Genomics and Clinical Genetics]
	King, Cillian [> >]
	Kortleven, Christian [> >]
	Huson, Vincent [> >]
	Kroon, Tim [> >]
	Kevenaar, Josta T. [> >]
	Schut, Desiree [> >]
	Saarloos, Ingrid [> >]
	Hoetjes, Joost P. [> >]
	de Wit, Heidi [> >]
	Stiedl, Oliver [> >]
	Spijker, Sabine [> >]
	Li, Ka Wan [> >]
	Mansvelder, Huibert D. [> >]
	Smit, August B. [> >]
	Cornelisse, Lennart Niels [> >]
	Verhage, Matthijs [> >]
	Toonen, Ruud F. [> >]
Publication date :	2016
Journal title :	The EMBO journal
Peer reviewed :	Yes (verified by ORBilu)
Audience :	International
ISSN :	0261-4189
e-ISSN :	1460-2075
Keywords :	[en] homeostatic regulation ; presynaptic strength ; synapse
Abstract :	[en] 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 mediatesCB1R- andmGluR2/3-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, preventingERK-dependent Munc18-1 phosphorylation increases synaptic strength.CB1R- andmGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced uponERK/MEKpathway inhibition and further reduced whenERK-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.
Permalink :	http://hdl.handle.net/10993/26826
DOI :	10.15252/embj.201592244
Other URL :	http://emboj.embopress.org/content/early/2016/04/07/embj.201592244.long
Commentary :	(c) 2016 The Authors.

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