Abstract
In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors—which are the gatekeepers to neurotransmission—remains unclear. One of the candidate Ca2+ sensors in release is the synaptic Ca2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca2+ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.
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Acknowledgements
We thank I. Herfort, I. Leznicki and A. Roth for technical assistance; H. Riedesel, J. Krause, S. Röcklin and the ARC in Dallas for help with mouse husbandry; and E. Neher, G. Alvarez de Toledo, J. López-Barneo and R. Jahn for advice. This study was supported by grants from the NIH to J.R., a grant from the Deutsche Forschungsgemeinschaft to C.R., Heisenberg Fellowships from the Deutsche Forschungsgemeinschaft to N.B. and C.R., a grant from the Perot Family Foundation to T.C.S., and postdoctoral fellowships from the Spanish Ministry of Education and the Fulbright Commission to R.F.C., and from the Deutsche Forschungsgemeinschaft to S.H.G.
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Fernández-Chacón, R., Königstorfer, A., Gerber, S. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410, 41–49 (2001). https://doi.org/10.1038/35065004
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DOI: https://doi.org/10.1038/35065004
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