Abstract
Inositol pyrophosphates such as IP7 (5-diphosphoinositol pentakisphosphate) are highly energetic inositol metabolites containing pyrophosphate bonds. While IP7 are known to regulate various biological events like metabolism, the molecular site of IP7 action in vesicle trafficking remains elusive. Here, we showed that IP7 potently inhibits synaptic vesicle exocytosis in both invitro reconstitution and cell culture settings. IP7 was identified as a high-affinity ligand for synaptotagmin 1 (Syt1), a calcium sensor essential for membrane fusion. Interactions of IP7 with Syt1 reduced the binding between Syt1 and Ca2+ as well as endowed Syt1 with its own negative effect, thereby suppressing Syt1 activation. These findings reveal a role of IP7 as an inhibitor of the exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.
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