Journal
SCIENCE
Volume 321, Issue 5895, Pages 1507-1510Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1163174
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Funding
- Deutsche Forschungsgemeinschaft [GE1042/1-1, GE1042/3-1, GE1042/3-2, Ro1296/5-3]
- NIH [NS051262, NS37200]
- Netherlands Organization for Scientific Research [GpD970-10-036, GpD900-01-001, GpD916-36-043]
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During synaptic vesicle fusion, the soluble N- ethylmaleimide- sensitive factor- attachment protein receptor ( SNARE) protein syntaxin- 1 exhibits two conformations that both bind to Munc18- 1: a closed conformation outside the SNARE complex and an open conformation in the SNARE complex. Although SNARE complexes containing open syntaxin- 1 and Munc18- 1 are essential for exocytosis, the function of closed syntaxin- 1 is unknown. We generated knockin/knockout mice that expressed only open syntaxin- 1B. Syntaxin- 1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18- 1 to syntaxin- 1 was impaired in syntaxin- 1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, the closed conformation of syntaxin- 1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE- complex/ Munc18- 1 assemblies.
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