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Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses.

ABSTRACT: The coordination of synaptic vesicle exocytosis and endocytosis supports neurotransmitter release from presynaptic terminals. Although inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (5-IP7), are versatile signaling metabolites in many biological events, physiological actions of 5-IP7 on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP7 in synaptic transmission in hippocampal brain slices from inositol hexakisphosphate kinase 1 (Ip6k1)-knockout mice. We found that presynaptic release probability was significantly increased in Ip6k1-knockout neurons, implying enhanced activity-dependent synaptic vesicle exocytosis. Expression of wild-type but not catalytically inactive IP6K1 in the Ip6k1-knockout hippocampus restored the altered presynaptic release probability. Moreover, Ip6k1-knockout neurons were insensitive to folimycin, a vacuolar ATPase inhibitor, and dynasore, a dynamin inhibitor, suggesting marked impairment in synaptic endocytosis during exocytosis. Our findings collectively establish that IP6K1 and its product, 5-IP7, act as key physiological determinants for inhibition of presynaptic vesicle exocytosis and stimulation of endocytosis at central synapses.

SUBMITTER: Park SJ

PROVIDER: S-EPMC7132149 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses.

Park Seung Ju SJ Park Hoyong H Kim Min-Gyu MG Zhang Seungjae S Park Seung Eun SE Kim Seyun S Chung ChiHye C

iScience 20200322 4

The coordination of synaptic vesicle exocytosis and endocytosis supports neurotransmitter release from presynaptic terminals. Although inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (5-IP7), are versatile signaling metabolites in many biological events, physiological actions of 5-IP7 on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP7 in synaptic transmission in hippocampal brain slices from ino ...[more]

PMID: 32252022

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Project description:The social amoeba Dictyostelium discoideum was instrumental in the discovery and early characterization of inositol pyrophosphates, a class of molecules possessing highly-energetic pyrophosphate bonds. Inositol pyrophosphates regulate diverse biological processes and are attracting attention due to their ability to control energy metabolism and insulin signalling. However, inositol pyrophosphate research has been hampered by the lack of simple experimental procedures to study them. The recent development of polyacrylamide gel electrophoresis (PAGE) and simple staining to resolve and detect inositol pyrophosphate species has opened new investigative possibilities. This technology is now commonly applied to study in vitro enzymatic reactions. Here we employ PAGE technology to characterize the D. discoideum inositol pyrophosphate metabolism. Surprisingly, only three major bands are detectable after resolving acidic extract on PAGE. We have demonstrated that these three bands correspond to inositol hexakisphosphate (IP₆ or Phytic acid) and its derivative inositol pyrophosphates, IP₇ and IP₈. Biochemical analyses and genetic evidence were used to establish the genuine inositol phosphate nature of these bands. We also identified IP₉ in D. discoideum cells, a molecule so far detected only from in vitro biochemical reactions. Furthermore, we discovered that this amoeba possesses three different inositol pentakisphosphates (IP₅) isomers, which are largely metabolised to inositol pyrophosphates. Comparison of PAGE with traditional Sax-HPLC revealed an underestimation of the cellular abundance of inositol pyrophosphates by traditional methods. In fact our study revealed much higher levels of inositol pyrophosphates in D. discoideum in the vegetative state than previously detected. A three-fold increase in IP₈ was observed during development of D. discoideum a value lower that previously reported. Analysis of inositol pyrophosphate metabolism using ip6k null amoeba revealed the absence of developmentally-induced synthesis of inositol pyrophosphates, suggesting that the alternative class of enzyme responsible for pyrophosphate synthesis, PP-IP₅K, doesn't' play a major role in the IP₈ developmental increase.

Dataset Information

Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses.

Publications

Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses.

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