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

• Published in: Nature (London) 1999-08, Vol.400 (6746), p.757-760
• Main Authors: Littleton, J. Troy, Serano, Thomas L., Rubin, Gerald M., Ganetzky, Barry, Chapman, Edwin R.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Calcium; Calcium - metabolism; Calcium-Binding Proteins; Drosophila; Electrophysiology; Humanities and Social Sciences; Insects; letter; Liposomes - metabolism; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Molecular Sequence Data; multidisciplinary; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Nervous system; Protein Binding; Proteins; Recombinant Fusion Proteins - metabolism; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Synapses - physiology; Synaptic Vesicles - metabolism; Synaptotagmin I; Synaptotagmins; Tissue Distribution
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/23462

Communication within the nervous system is mediated by Ca 2+ -triggered fusion of synaptic vesicles with the presynaptic plasma membrane. Genetic and biochemical evidence indicates that synaptotagmin I may function as a Ca 2+ sensor in neuronal exocytosis because it can bind Ca 2+ and penetrate into lipid bilayers 1 , 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ -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.