In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 29 ( 2016-07-19), p. 8314-8319
Abstract:
Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP 7 ) 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-IP 7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP 7 levels, caused by overexpression of inositol hexakisphosphate (IP 6 ) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP 7 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-IP 7 , but not 1-IP 7 , exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP 6 . Synaptotagmin 1 (Syt1), a Ca 2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP 7 . Notably, 5-IP 7 showed a 45-fold higher binding affinity for Syt1 compared with IP 6 . In addition, 5-IP 7 –dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca 2+ levels. Thus, 5-IP 7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca 2+ . These findings reveal a role of 5-IP 7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1521600113
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2016
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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