Differential regulation of synchronous versus asynchronous neurotransmitter release by the C2 domains of synaptotagmin 1
Author(s)Yoshihara, Motojiro; Guan, Zhuo; Littleton, J. Troy
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Synaptic vesicle fusion at many synapses has been kinetically separated into two distinct Ca[superscript 2+]-dependent temporal components consisting of a rapid synchronous phase followed by a slower asynchronous component. Mutations in the synaptic vesicle Ca[superscript 2+] sensor Synaptotagmin 1 (Syt 1) reduce synchronous neurotransmission while enhancing the slower asynchronous phase of release. Syt 1 regulation of vesicle fusion requires interactions mediated by its tandem cytoplasmic C2 domains (C2A and C2B). Although Ca[superscript 2+] binding by Syt 1 is predicted to drive synchronous release, it is unknown if Ca[superscript 2+] interactions with either C2 domain is required for suppression of asynchronous release. To determine if Ca[superscript 2+] binding by Syt 1 regulates these two phases of release independently, we performed electrophysiological analysis of transgenically expressed Syt 1 mutated at Ca[superscript 2+] binding sites in C2A or C2B in the background of Drosophila Syt 1-null mutants. Transgenic animals expressing mutations that disrupt Ca[superscript 2+] binding to C2A fully restored the synchronous phase of neurotransmitter release, whereas the asynchronous component was not suppressed. In contrast, rescue with Ca[superscript 2+]-binding mutants in C2B displayed little rescue of the synchronous release component, but reduced asynchronous release. These results suggest that the tandem C2 domains of Syt 1 play independent roles in neurotransmission, as Ca[superscript 2+] binding to C2A suppresses asynchronous release, whereas Ca[superscript 2+] binding to C2B mediates synchronous fusion.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Yoshihara, M., Z. Guan, and J. T. Littleton. “Differential regulation of synchronous versus asynchronous neurotransmitter release by the C2 domains of synaptotagmin 1.” Proceedings of the National Academy of Sciences 107, no. 33 (August 17, 2010): 14869-14874.
Final published version