The Regulatory Role of Syntaxin 1 N-terminal Conformation in Vesicle Priming and Exocytosis

During vesicle priming at the central synapse, Syntaxin 1, together with SNAP25 and Synaptobrevin, assemble into the synaptic SNARE complex. The formation of SNARE complex is thought to provide the energy needed that enables vesicle exocytosis during Ca2+ triggering step at the presynapse. Among the SNARE proteins, Syntaxin 1 is thought to play a special role in regulating the rate of SNARE assembly by adopting two conformations; a closed autoinhibitory conformation in which core complex domain is hindered by N-terminal Habc domain, and an open conformation in which the SNARE motif of syntaxin is open and ready to interact with the other SNAREs.In the present study we examined the role of the conformational switch of syntaxin 1 by analyzing synaptic properties of genetically modified mice expressing a mutation that leaves syntaxin 1 in a constitutively open conformation. In cultured hippocampal neurons, the mutation led to a significant increase in the rate of vesicle priming, supporting the hypothesis that syntaxin 1 regulates vesicle priming during the SNARE complex assembly process. Surprisingly, we also found that the mutation led to an increase in synaptic release probability, suggesting that the conformation of syntaxin 1 also regulates vesicle fusion by reducing the energy barrier of vesicle fusion to the plasma membrane. Our data support the idea that the SNARE complex member syntaxin 1 and its individual conformations are crucial regulators of the efficacy and short-term plasticity of synaptic transmission.