Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis.

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

doi:10.1073/pnas.1521600113

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Journal article

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis.

Lee TS Department of Physics, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Yonsei University, Seoul 30722, Korea; Yonsei-IBS Institute, Yonsei University, Seoul 30722, Korea;
Lee JY Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea;
Kyung JW Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea;
Yang Y Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Korea;
Park SJ Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea;
Lee S Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea;
Pavlovic I Department of Chemistry, University of Zurich, 8057 Zurich, Switzerland;
Kong B Department of Genetic Engineering and Center for Human Interface Nanotechnology, Sungkyunkwan University, Suwon 16419, Korea;
Jho YS Asia-Pacific Center for Theoretical Physics, Pohang, Gyeongbuk 37673, Korea;
Jessen HJ Institute of Organic Chemistry, Albert-Ludwigs-University Freiburg, Freiburg 79104, Germany;
Kweon DH Department of Genetic Engineering and Center for Human Interface Nanotechnology, Sungkyunkwan University, Suwon 16419, Korea;
Shin YK Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011;
Kim SH Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea; Department of Physiology, School of Medicine, Neurodegeneration Control Research Center, Kyung Hee University, Seoul 02447, Korea; sunghyunkim@khu.ac.kr tyyoon@yonsei.ac.kr seyunkim@kaist.ac.kr.
Yoon TY Center for Nanomedicine, Institute for Basic Science (IBS), Yonsei University, Seoul 30722, Korea; Yonsei-IBS Institute, Yonsei University, Seoul 30722, Korea; sunghyunkim@khu.ac.kr tyyoon@yonsei.ac.kr seyunkim@kaist.ac.kr.
Kim S Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; Korea Advanced Institute of Science and Technology Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea sunghyunkim@khu.ac.kr tyyoon@yonsei.ac.kr seyunkim@kaist.ac.kr.

2016-07-02

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Proceedings of the National Academy of Sciences of the United States of America. - 2016

Phosphotransferases (Phosphate Group Acceptor)

English 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.

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