References of "Kevenaar, Josta T"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailPresynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.
Schmitz, Sabine UL; King, Cillian; Kortleven, Christian et al

in The EMBO journal (2016)

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by ... [more ▼]

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. [less ▲]

Detailed reference viewed: 65 (7 UL)
Full Text
Peer Reviewed
See detailLiprin-alpha2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission.
Spangler, Samantha A.; Schmitz, Sabine UL; Kevenaar, Josta T. et al

in The Journal of cell biology (2013), 201(6), 915-28

The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold ... [more ▼]

The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-alpha2 as a key organizer in this process. We show that liprin-alpha2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-alpha2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-alpha2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-alpha2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-alpha2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-alpha2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. [less ▲]

Detailed reference viewed: 45 (6 UL)