NDLI: Inositol hexakisphosphate suppresses excitatory neurotransmission via synaptotagmin-1 C2B domain in the hippocampal neuron

Content Provider	PubMed Central
Author	Yang, Shao-nian Shi, Yue Yang, Guang Li, Yuxin Yu, Lina Shin, Ok-ho Bacaj, Taulant Südhof, Thomas C. Yu, Jia Berggren, Per-olof
Abstract	Inositol hexakisphosphate (InsP6) levels rise and fall with neuronal excitation and silence, respectively, in the hippocampus, suggesting potential signaling functions of this inositol polyphosphate in hippocampal neurons. We now demonstrate that intracellular application of InsP6 caused a concentration-dependent inhibition of autaptic excitatory postsynaptic currents (EPSCs) in cultured hippocampal neurons. The treatment did not alter the size and replenishment rate of the readily releasable pool in autaptic neurons. Intracellular exposure to InsP6 did not affect spontaneous EPSCs or excitatory amino acid-activated currents in neurons lacking autapses. The InsP6-induced inhibition of autaptic EPSCs was effectively abolished by coapplication of an antibody to synaptotagmin-1 C2B domain. Importantly, preabsorption of the antibody with a GST-WT synaptotagmin-1 C2B domain fragment but not with a GST-mutant synaptotagmin-1 C2B domain fragment that poorly reacted with the antibody impaired the activity of the antibody on the InsP6-induced inhibition of autaptic EPSCs. Furthermore, K+ depolarization significantly elevated endogenous levels of InsP6 and occluded the inhibition of autaptic EPSCs by exogenous InsP6. These data reveal that InsP6 suppresses excitatory neurotransmission via inhibition of the presynaptic synaptotagmin-1 C2B domain-mediated fusion via an interaction with the synaptotagmin Ca2+-binding sites rather than via interference with presynaptic Ca2+ levels, synaptic vesicle trafficking, or inactivation of postsynaptic ionotropic glutamate receptors. Therefore, elevated InsP6 in activated neurons serves as a unique negative feedback signal to control hippocampal excitatory neurotransmission.
Related Links	http://dx.doi.org/10.1073/pnas.1115070109
Starting Page	12183
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	30
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-07-24
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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