Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line

S. Hauke, A. K. Dutta, V. B. Eisenbeis, D. Bezold, T. Bittner, C. Wittwer, D. Thakor, I. Pavlovic, Carsten Schultz, H. J. Jessen

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Abstract

Among many cellular functions, inositol pyrophosphates (PP-InsPs) are metabolic messengers involved in the regulation of glucose uptake, insulin sensitivity, and weight gain. However, their mechanisms of action are still poorly understood. So far, the influence of PP-InsPs on cellular metabolism has been studied by overexpression or knockout/inhibition of relevant metabolizing kinases (IP6Ks, PPIP5Ks). These approaches are, inter alia, limited by time-resolution and potential compensation mechanisms. Here, we describe the synthesis of cell-permeant caged PP-InsPs as tools to rapidly modulate intracellular levels of defined isomers of PP-InsPs in a genetically non-perturbed cellular environment. We show that caged prometabolites readily enter live cells where they are enzymatically converted into still inactive, metabolically stable, photocaged PP-InsPs. Upon light-triggered release of 5-PP-InsP 5 , the major cellular inositol pyrophosphate, oscillations of intracellular Ca 2+ levels in MIN6 cells were transiently reduced to spontaneously recover again. In contrast, uncaging of 1-PP-InsP 5 , a minor cellular isomer, was without effect. These results provide evidence that PP-InsPs play an active role in regulating [Ca 2+ ] i oscillations, a key element in triggering exocytosis and secretion in β-cells.

Original languageEnglish (US)
Pages (from-to)2687-2692
Number of pages6
JournalChemical Science
Volume10
Issue number9
DOIs
Publication statusPublished - Jan 1 2019

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ASJC Scopus subject areas

  • Chemistry(all)

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Hauke, S., Dutta, A. K., Eisenbeis, V. B., Bezold, D., Bittner, T., Wittwer, C., ... Jessen, H. J. (2019). Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line. Chemical Science, 10(9), 2687-2692. https://doi.org/10.1039/c8sc03479f