Tyrosine phosphorylation of Munc18-1 inhibits synaptic transmission by preventing SNARE assembly

ABSTRACT: Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src-family kinases (SFKs). Phospho-mimetic Y473D mutation of an SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ('SNARE-templating') and membrane fusion in vitro. Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D. Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming. On the other

SUBMITTER: Bernhard Dörr 

PROVIDER: S-SCDT-MSBTEST-18-292V1 | biostudies-other |

REPOSITORIES: biostudies-other