Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

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Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7-dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.
Publisher
NATL ACAD SCIENCES
Issue Date
2016-07
Language
English
Article Type
Article
Keywords

SQUID GIANT SYNAPSE; MEMBRANE-FUSION; C2B DOMAIN; NEUROTRANSMITTER RELEASE; DIPHOSPHOINOSITOL POLYPHOSPHATES; NERVE-TERMINALS; VESICLE FUSION; HEXAKISPHOSPHATE; CELLS; TRANSMISSION

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.113, no.29, pp.8314 - 8319

ISSN
0027-8424
DOI
10.1073/pnas.1521600113
URI
http://hdl.handle.net/10203/212921
Appears in Collection
BS-Journal Papers(저널논문)
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