Regulation of Vesicle Fusion at the Synapse

The controlled release of neurotransmitters is central to information processing in the nervous system, and is altered in many psychiatric and neurological disorders. The minimal protein machinery for this process (the clamp/activator Complexin, the calcium sensor Synaptotagmin, and the synaptic SNAREs VAMP2, Syntaxin1 and SNAP25) has been known for a while. Yet it is still not understood how the entry of calcium at nerve endings triggers the synchronous release of neurotransmitters that physiology requires.

Recent structural and biochemical studies done in our lab has suggested a novel and detailed structural /biochemical working model to explain the synchronous release of neurotransmitters occurs (shown on the right).

Currently, we are employing a variety of biochemical, spectroscopic (including single event/single molecule optical techniques) and structural techniques to probe this model and its implication using completely defined system, along with genetic correlations in Drosophila to validate the physiological significance of key findings when possible. We aim to establish the functional, compositional, and dynamic properties of the clamped zig-zag array of Complexin and SNAREpins as it occurs at vesicle-bilayer junctions, and how the calcium sensor Synaptotagmin trigger exocytosis from this clamped state.