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

被引：35

作者：

Schmitz, Sabine K. ^{[1
,2
]}

King, Cillian ^{[1
,2
]}

Kortleven, Christian ^{[2
,3
]}

Huson, Vincent ^{[1
,2
]}

Kroon, Tim ^{[2
,3
]}

Kevenaar, Josta T. ^{[1
,2
]}

Schut, Desiree ^{[1
,2
]}

Saarloos, Ingrid ^{[1
,2
]}

Hoetjes, Joost P. ^{[1
,2
]}

de Wit, Heidi ^{[1
,2
]}

Stiedl, Oliver ^{[1
,2
,4
]}

Spijker, Sabine ^{[2
,4
]}

Li, Ka Wan ^{[2
,4
]}

Mansvelder, Huibert D. ^{[2
,3
]}

Smit, August B. ^{[2
,4
]}

Cornelisse, Lennart Niels ^{[1
,2
]}

Verhage, Matthijs ^{[1
,2
]}

Toonen, Ruud F. ^{[1
,2
]}

机构：

[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom & Clin Genet, Neurosci Campus Amsterdam, Amsterdam, Netherlands

[2] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Integrat Neurophysiol, Neurosci Campus Amsterdam, Amsterdam, Netherlands

[4] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, Neurosci Campus Amsterdam, Amsterdam, Netherlands

来源：

EMBO JOURNAL | 2016年 / 35卷 / 11期

关键词：

homeostatic regulation; presynaptic strength; synapse; METABOTROPIC GLUTAMATE RECEPTORS; READILY RELEASABLE POOL; UBIQUITIN-PROTEASOME SYSTEM; SIGNAL-REGULATED KINASE; PAIRED-PULSE DEPRESSION; SYNAPTIC PLASTICITY; HIPPOCAMPAL SYNAPSES; GROUP-II; NEUROTRANSMITTER RELEASE; PROTEIN-KINASE;

D O I：

10.15252/embj.201592244

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1236 / 1250

页数：15

共 76 条

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