title: Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.
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.
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Sabine K
authors.initials: SK
authors.lastname: Schmitz
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Cillian
authors.initials: C
authors.lastname: King
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Kortleven
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: Huson
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Kroon
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Josta T
authors.initials: JT
authors.lastname: Kevenaar
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Desiree
authors.initials: D
authors.lastname: Schut
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Saarloos
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Joost P
authors.initials: JP
authors.lastname: Hoetjes
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Heidi
authors.initials: H
authors.lastname: de Wit
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stiedl
authors.affiliation: Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.affiliation: Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Huibert D
authors.initials: HD
authors.lastname: Mansvelder
authors.affiliation: Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Lennart Niels
authors.initials: LN
authors.lastname: Cornelisse
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands matthijs.verhage@cncr.vu.nl ruud.toonen@cncr.vu.nl.
authors.forename: Matthijs
authors.identifier: 0000-0002-2514-0216
authors.initials: M
authors.lastname: Verhage
authors.affiliation: Department of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit (VU) and VU Medical Center, Amsterdam, The Netherlands matthijs.verhage@cncr.vu.nl ruud.toonen@cncr.vu.nl.
authors.forename: Ruud F
authors.identifier: 0000-0002-9900-4233
authors.initials: RF
authors.lastname: Toonen
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051938:Munc18 Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D011247:Pregnancy; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D051938:Munc18 Proteins; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D020928:Mitogen-Activated Protein Kinases
keywords: homeostatic regulation; presynaptic strength; synapse