title: Synaptotagmin-1 and synaptotagmin-7 trigger synchronous and asynchronous phases of neurotransmitter release.
abstract: In forebrain neurons, knockout of synaptotagmin-1 blocks fast Ca(2+)-triggered synchronous neurotransmitter release but enables manifestation of slow Ca(2+)-triggered asynchronous release. Here, we show using single-cell PCR that individual hippocampal neurons abundantly coexpress two Ca(2+)-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 Ca(2+)-binding sites. Even in synaptotagmin-1-containing neurons, synaptotagmin-7 ablation partly impaired asynchronous release induced by extended high-frequency stimulus trains. Synaptotagmins bind Ca(2+) via two C2 domains, the C2A and C2B domains. Surprisingly, synaptotagmin-7 function selectively required its C2A domain Ca(2+)-binding sites, whereas synaptotagmin-1 function required its C2B domain Ca(2+)-binding sites. Our data show that nearly all Ca(2+)-triggered release at a synapse is due to synaptotagmins, with synaptotagmin-7 mediating a slower form of Ca(2+)-triggered release that is normally occluded by faster synaptotagmin-1-induced release but becomes manifest upon synaptotagmin-1 deletion.
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Taulant
authors.initials: T
authors.lastname: Bacaj
authors.forename: Dick
authors.initials: D
authors.lastname: Wu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yang
authors.forename: Wade
authors.initials: W
authors.lastname: Morishita
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D050863:Synaptotagmin I / Q000235:genetics / Q000502:physiology*; D050857:Synaptotagmins / Q000235:genetics / Q000502:physiology*
chemical_list: D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D050863:Synaptotagmin I; D050857:Synaptotagmins; D002118:Calcium