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Synaptic function modulated by changes in the ratio of synaptotagmin I and IV

Abstract

Communication within the nervous system is mediated by Ca2+-triggered fusion of synaptic vesicles with the presynaptic plasma membrane. Genetic and biochemical evidence indicates that synaptotagmin I may function as a Ca2+ sensor in neuronal exocytosis because it can bind Ca2+ and penetrate into lipid bilayers1,2,3,4. Chronic depolarization or seizure activity results in the upregulation of a distinct and unusual isoform of the synaptotagmin family, synaptotagmin IV (ref. 5). We have identified a Drosophila homologue of synaptotagmin IV that is enriched on synaptic vesicles and contains an evolutionarily conserved substitution of aspartate to serine that abolishes its ability to bind membranes in response to Ca2+ influx. Synaptotagmin IV forms hetero-oligomers with synaptotagmin I, resulting in synaptotagmin clusters that cannot effectively penetrate lipid bilayers and are less efficient at coupling Ca2+ to secretion in vivo : upregulation of synaptotagmin IV, but not synaptotagmin I, decreases evoked neurotransmission. These findings indicate that modulating theexpression of synaptotagmins with different Ca2+-binding affinities can lead to heteromultimers that can regulate the efficiency of excitation–secretion coupling in vivo and represent a new molecular mechanism for synaptic plasticity.

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Figure 1: Identification of the Drosophila synaptotagmin family.
Figure 2: Synaptotagmin IV is a synaptic vesicle protein.
Figure 3: Hetero-oligomerization of Drosophila synaptotagmins I and IV decreases membrane binding.
Figure 4: Electrophysiological analysis of transgenic Drosophila overexpressing synaptotagmin IV or synaptotagmin I.

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Acknowledgements

We thank R. Kelly, S. Benzer, L. Brodin, C. Goodman, W. Caterall, H. Jackle and R.Jahn for antibodies and reagents, and J. Pendleton for help with sequencing. This work was supported by grants from the NIH and the Howard Hughes Medical Institute. T.L.S. is a Jane Coffin Childs postdoctoral fellow. J.T.L. is a Merck fellow of the Helen Hay Whitney Foundation.

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Correspondence to J. Troy Littleton.

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Littleton, J., Serano, T., Rubin, G. et al. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400, 757–760 (1999). https://doi.org/10.1038/23462

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