Molecular Mechanisms of Calcium-Evoked Synchronous Neurotransmitter Release

The controlled yet rapid release of neurotransmitters stored in synaptic vesicles (SV) is central to all information processing in the brain and is altered in many neurological disorders. This process relies on an efficient coupling of SV fusion to action potential (AP)-evoked Ca2+ influx.

It is well-established that SV fusion is catalysed by the synaptic SNARE proteins and is tightly regulated by Ca2+ sensing protein, Synaptotagmin-1 to enable neurotransmitter release with millisecond precision. How this occurs in molecular terms is unknown.

The main goal of the proposed research is to determine the molecular mechanisms that allow synchronization of SV fusion to APs.

In particular, I aim to (i) delineate the minimal protein machinery required for Ca2+-evoked vesicular release and (ii) determine the precise Ca2+-activation mechanism.I propose to use a ´reductionist´ approach involving a reconstituted, biochemically-defined fusion system combined with systematic mutations in the constituent proteins and perform the research at Yale University for 3-years.

Specifically, I will generate calcium transients mimicking presynaptic calcium dynamics and systematically test how these calcium signals shape the vesicular release probability and kinetics under different molecular reconstitution conditions.

This work will reveal the molecular mechanism underlying the Ca2+ control of neurotransmitter release and proceed toward building a universal mechanistic model of synaptic transmission.