Lee TS Lee JY Kyung JW Yang Y Park SJ Lee S Pavlovic I Kong B Jho YS Jessen HJ Kweon DH Shin YK Kim SH Yoon TY Kim S 2016 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 Ca(2+) 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 Ca(2+) levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca(2+) 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. application/pdf https://sonar.ch/global/documents/252354 eng info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1521600113 info:eu-repo/semantics/altIdentifier/pmid/27364007 info:eu-repo/semantics/openAccess Proceedings of the National Academy of Sciences of the United States of America. - 2016 inositol pyrophosphate synaptic vesicle exocytosis synaptotagmin Animals Exocytosis Hippocampus Inositol Phosphates Neurons PC12 Cells Phosphotransferases (Phosphate Group Acceptor) Rats Rats, Sprague-Dawley Synaptotagmin I Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis. http://purl.org/coar/resource_type/c_6501