The role of Syntaxin-1 in vesicle docking, -priming and neurotransmitter release at central synapses

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The synaptic protein Syntaxin-1 (Stx1) is fundamental for neurotransmitter release, but important aspects of its function are poorly understood. We recently have shown that Syntaxin-1 is critical for every step from vesicle docking, vesicle priming and vesicle fusion at mammalian synapses by using a new Stx1A/1B double deficient mouse model. To gain insights in Stx1 diverse functions we will perform site directed mutagenesis in a gain of function rescue approach and combine this with electrophysiological, biochemical, ultrastructural and high resolution light microscopy imaging analyses. In the first aim we will focus on the role of the polybasic linker region between Transmembrane- and SNARE-Complex domains. We will furthermore perform analysis to decipher the mechanistical basis of the evoked and spontaneous neurotransmitter release. Comparative analysis of Stx1 with other STX isoforms will define the important secondary structural motifs responsible for the differential regulation of these two forms of release. These studies will provide important mechanistic insights in the fundamental process of neurotransmitter release.