Photolysis of Caged Inositol Pyrophosphate InsP8Directly Modulates Intracellular Ca2+Oscillations and Controls C2AB Domain Localization

Tamara Bittner, Christopher Wittwer, Sebastian Hauke, Daniel Wohlwend, Stephan Mundinger, Amit K. Dutta, Dominik Bezold, Tobias Dürr, Thorsten Friedrich, Carsten Schultz, Carsten Schultz, Henning J. Jessen, Henning J. Jessen, Henning J. Jessen

Research output: Contribution to journalArticle

Abstract

Inositol pyrophosphates constitute a family of hyperphosphorylated signaling molecules involved in the regulation of glucose uptake and insulin sensitivity. While our understanding of the biological roles of inositol heptaphosphates (PP-InsP5) has greatly improved, the functions of the inositol octaphosphates ((PP)2-InsP4) have remained unclear. Here we present the synthesis of two enantiomeric cell-permeant and photocaged (PP)2-InsP4 derivatives and apply them to study the functions in living β-cells. Photorelease of the naturally occurring isomer 1,5-(PP)2-InsP4 led to an immediate and concentration-dependent reduction of intracellular calcium oscillations, while other caged inositol pyrophosphates (3,5-(PP)2-InsP4, 5-PP-InsP5, 1-PP-InsP5, 3-PP-InsP5) showed no immediate effect. Furthermore, uncaging of 1,5-(PP)2-InsP4 but not 3,5-(PP)2-InsP4 induced translocation of the C2AB domain of granuphilin from the plasma membrane to the cytosol. Granuphilin is involved in membrane docking of secretory vesicles. This suggests that 1,5-(PP)2-InsP4 impacts β-cell activity by regulating granule localization and/or priming and calcium signaling in concert.

Original languageEnglish (US)
Pages (from-to)10606-10611
Number of pages6
JournalJournal of the American Chemical Society
Volume142
Issue number24
DOIs
StatePublished - Jun 17 2020

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Bittner, T., Wittwer, C., Hauke, S., Wohlwend, D., Mundinger, S., Dutta, A. K., Bezold, D., Dürr, T., Friedrich, T., Schultz, C., Schultz, C., Jessen, H. J., Jessen, H. J., & Jessen, H. J. (2020). Photolysis of Caged Inositol Pyrophosphate InsP8Directly Modulates Intracellular Ca2+Oscillations and Controls C2AB Domain Localization. Journal of the American Chemical Society, 142(24), 10606-10611. https://doi.org/10.1021/jacs.0c01697