TY - JOUR
T1 - Synaptotagmin-1 and Synaptotagmin-7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release
AU - Bacaj, Taulant
AU - Wu, Dick
AU - Yang, Xiaofei
AU - Morishita, Wade
AU - Zhou, Peng
AU - Xu, Wei
AU - Malenka, Robert C.
AU - Südhof, Thomas C.
N1 - Funding Information:
We thank E. Chapman (UW Madison) for providing Doc2A and Doc2B shRNAs and Ira Huryeva for excellent technical support. This paper was supported by an NINDS NRSA fellowship (F32NS067896 to T.B.) and by grants from the NIH (P50 MH086403 and R01 NS077906 to R.C.M. and T.C.S.).
PY - 2013/11/20
Y1 - 2013/11/20
N2 - 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 coexpress 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.
AB - 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 coexpress 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.
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U2 - 10.1016/j.neuron.2013.10.026
DO - 10.1016/j.neuron.2013.10.026
M3 - Article
C2 - 24267651
AN - SCOPUS:84887001711
SN - 0896-6273
VL - 80
SP - 947
EP - 959
JO - Neuron
JF - Neuron
IS - 4
ER -