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We investigate how neurotransmitters are released by calcium-evoked synaptic vesicle exocytosis and how release is regulated during presynaptic plasticity processes that underlie very diverse forms of information processing in the brain. We use a wide variety of biophysical approaches, including NMR spectroscopy, X-ray crystallography, cryo-EM, molecular dynamics simulations and liposome fusion assays, among others. Collaborations with Thomas Sudhof, Christian Rosenmund and other neurobiologists allow us to correlate our in vitro studies with physiological data. The importance of this research was emphasized by the award of the 2013 Nobel Prize in Physiology or Medicine to Thomas Südhof, James Rothman and Randy Schekman.

Our lab reconstituted synaptic vesicle fusion with the most central components of the neurotransmitter release machinery [1,2], which, together with results from other groups, defined the functions of these components (color coded in the image above) [reviewed in ref. 3]. The SNARE proteins syntaxin (yellow and orange), synaptobrevin (red) and SNAP-25 (green) mediate membrane fusion by forming a tight SNARE complex that brings the vesicle and plasma membranes together, and that is disassembled by NSF and SNAPs (not shown). Munc18 (violet) binds to a self-inhibited ‘closed’ conformation of syntaxin-1 (on the right) and organizes SNARE complex assembly in an NSF-SNAP-resistant manner together with Munc13 (cyan), which bridges the vesicle and plasma membranes (on the left) and helps to open syntaxin. Synaptotagmin (blue) acts as the Ca2+ sensor that triggers release in a tight interplay with the SNAREs and complexin (pink).

 

Current efforts in the lab are directed at addressing fundamental questions that remain unanswered about how Ca2+ sensing by synaptotagmin-1 triggers release, how the SNAREs mediate membrane fusion, and how Munc18 and Munc13 orchestrate SNARE complex assembly. Our research is in a very exciting moment because we believe that we will be able to answer these questions in a near future. As the basic steps leading to release are elucidated, we will place more emphasis on already ongoing efforts to investigate the mechanisms underlying presynaptic plasticity.

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[1] Ma, C., Su, L., Seven, A. B., Xu, Y., and Rizo, J. (2013) Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release, Science 339, 421-425.
[2] Liu, X., Seven, A. B., Camacho, M., Esser, V., Xu, J., Trimbuch, T., Quade, B., Su, L., Ma, C., Rosenmund, C., and Rizo, J. (2016) Functional synergy between the Munc13 C-terminal C1 and C2 domains, elife 5, e13696.
[3] Rizo, J. (2018) Mechanism of neurotransmitter release coming into focus, Protein Sci 27, 1364-1391.