Helen & Robert Appel Alzheimer’s Disease Research Institute

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TitleSynaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles.
Publication TypeJournal Article
Year of Publication2015
AuthorsBacaj T, Wu D, Burré J, Malenka RC, Liu X, Südhof TC
JournalPLoS Biol
Date Published2015 Oct
KeywordsAnimals, Animals, Newborn, Binding Sites, Calcium Signaling, Cells, Cultured, Excitatory Postsynaptic Potentials, HEK293 Cells, Hippocampus, Humans, Inhibitory Postsynaptic Potentials, Mice, Knockout, Mutation, Nerve Tissue Proteins, Neurons, Recombinant Proteins, RNA Interference, SNARE Proteins, Synaptic Vesicles, Synaptotagmin I, Synaptotagmins

In forebrain neurons, Ca(2+) triggers exocytosis of readily releasable vesicles by binding to synaptotagmin-1 and -7, thereby inducing fast and slow vesicle exocytosis, respectively. Loss-of-function of synaptotagmin-1 or -7 selectively impairs the fast and slow phase of release, respectively, but does not change the size of the readily-releasable pool (RRP) of vesicles as measured by stimulation of release with hypertonic sucrose, or alter the rate of vesicle priming into the RRP. Here we show, however, that simultaneous loss-of-function of both synaptotagmin-1 and -7 dramatically decreased the capacity of the RRP, again without altering the rate of vesicle priming into the RRP. Either synaptotagmin-1 or -7 was sufficient to rescue the RRP size in neurons lacking both synaptotagmin-1 and -7. Although maintenance of RRP size was Ca(2+)-independent, mutations in Ca(2+)-binding sequences of synaptotagmin-1 or synaptotagmin-7--which are contained in flexible top-loop sequences of their C2 domains--blocked the ability of these synaptotagmins to maintain the RRP size. Both synaptotagmins bound to SNARE complexes; SNARE complex binding was reduced by the top-loop mutations that impaired RRP maintenance. Thus, synaptotagmin-1 and -7 perform redundant functions in maintaining the capacity of the RRP in addition to nonredundant functions in the Ca(2+) triggering of different phases of release.

Alternate JournalPLoS Biol.
PubMed ID26437117
PubMed Central IDPMC4593569
Grant ListK99 MH107618 / MH / NIMH NIH HHS / United States
MH086403 / MH / NIMH NIH HHS / United States
MH100752 / MH / NIMH NIH HHS / United States
NS077906 / NS / NINDS NIH HHS / United States
NS08708601 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States