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Synaptotagmin-1 and -7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release

Bacaj, T., Wu, D., Yang, X., Morishita, W., Zhou, P., Xu, W., Malenka, R.C., Südhof, T.C.

In forebrain neurons, knockout of synaptotagmin-1 blocks fast Ca2+-triggered synchronous neurotransmitter release, but enables manifestation of slow Ca2+-triggered asynchronous release. Here, we show using single-cell PCR that individual hippocampal neurons abundantly co-express two Ca2+-binding synaptotagmin isoforms, synaptotagmin-1 and synaptotagmin-7. In synaptotagmin-1 deficient synapses of excitatory and inhibitory neurons, loss-of-function of synaptotagmin-7 suppressed asynchronous release. This phenotype was rescued by wild-type but not mutant synaptotagmin-7 lacking functional Ca2+-binding sites. Even in synaptotagmin-1 containing neurons, synaptotagmin-7 ablation partly impaired asynchronous release induced by extended high-frequency stimulus trains. Synaptotagmins bind Ca2+ via two C2-domains, the C2A- and C2B-domains. Surprisingly, synaptotagmin-7 function selectively required its C2A-domain Ca2+-binding sites, whereas synaptotagmin-1 function required its C2B-domain Ca2+-binding sites. Our data show that nearly all Ca2+-triggered release at a synapse is due to synaptotagmins, with synaptotagmin-7 mediating a slower form of Ca2+-triggered release that is normally occluded by faster synaptotagmin-1-induced release, but becomes manifest upon synaptotagmin-1 deletion.

Citation

Bacaj, T., Wu, D., Yang, X., Morishita, W., Zhou, P., Xu, W., Malenka, R.C., Südhof, T.C. "Synaptotagmin-1 and -7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release" Neuron (2013): 947–59