Abstract

Inositol pyrophosphates (PP-IPs) regulate diverse physiological processes; to better understand their functional roles, assessing their tissue-specific distribution is important. Here, we profiled PP-IP levels in mammalian organs using a novel HILIC-MS/MS protocol and discovered that the gastrointestinal tract (GIT) contained the highest levels of IP7 and its precursor IP6. Although their absolute levels in the GIT is diet-dependent, elevated IP7 metabolism still exists under dietary regimes devoid of exogenous IP7. Of the major GIT cells, enteric neurons selectively express the IP7-synthesizing enzyme IP6K2. IP6K2-knockout mice exhibited significantly impaired IP7 metabolism in the various organs including the proximal GIT. Additionally, HILIC-MS/MS analysis displayed that genetic ablation of IP6K2 significantly impaired IP7 metabolism in the gut and duodenal muscularis externa containing myenteric plexus. Whole transcriptome analysis of duodenal muscularis externa further suggested that IP6K2 inhibition induced the gene sets associated with mature neurons such as inhibitory, GABAergic and dopaminergic neurons, concomitantly with suppression of those for neural progenitor/stem cells and glial cells. In addition, IP6K2 inhibition explicitly affected transcript levels of certain genes modulating neuronal differentiation and functioning, implying critical roles of IP6K2-IP7 axis in developmental and functional regulation of enteric nervous system. These results collectively reveal an unexpected role of mammalian IP7—a highly active IP6K2-IP7 pathway is conducive to enteric nervous system.

Competing Interest Statement

The authors have declared no competing interest.

Details

Title
Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in enteric nervous system
Author
Ito, Masatoshi; Fujii, Natsuko; Kohara, Saori; Hori, Shuho; Tanaka, Masayuki; Wittwer, Christopher; Kikuchi, Kenta; Iijima, Takatoshi; Kakimoto, Yu; Hirabayashi, Kenichi; Kurotaki, Daisuke; Henning Jacob Jessen; Saiardi, Adolfo; Nagata, Eiichiro
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2022
Publication date
Sep 19, 2022
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2715617450
Copyright
© 2022. This article is published under http://creativecommons.org/licenses/by-nd/4.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.