Abstract
Spontaneous 'mini' release occurs at all synapses, but its nature remains enigmatic. We found that >95% of spontaneous release in murine cortical neurons was induced by Ca2+-binding to synaptotagmin-1 (Syt1), the Ca2+ sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca2+-dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca2+ dependent but was activated at lower Ca2+ concentrations and with a lower Ca2+ cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca2+ sensor for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca2+ sensor for spontaneous release that resembles the Ca2+ sensor for evoked asynchronous release. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.
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Acknowledgements
We thank I. Kornblum, J. Mitchell, L. Fan and A. Roth for excellent technical assistance, and A. Maximov and C. Zhang for advice.
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J.X., Z.P.P. and O.-H.S. planned, performed and analyzed the experiments. T.C.S. conceived the project, supervised the experiments and wrote the paper.
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Xu, J., Pang, Z., Shin, OH. et al. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nat Neurosci 12, 759–766 (2009). https://doi.org/10.1038/nn.2320
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DOI: https://doi.org/10.1038/nn.2320
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