Photolysis of Caged Inositol Pyrophosphate InsP Directly Modulates Intracellular Ca Oscillations and Controls C2AB Domain Localization.

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-InsP) has greatly improved, the functions of the inositol octaphosphates ((PP)-InsP) have remained unclear. Here we present the synthesis of two enantiomeric cell-permeant and photocaged (PP)-InsP derivatives and apply them to study the functions in living β-cells. Photorelease of the naturally occurring isomer 1,5-(PP)-InsP led to an immediate and concentration-dependent reduction of intracellular calcium oscillations, while other caged inositol pyrophosphates (3,5-(PP)-InsP, 5-PP-InsP, 1-PP-InsP, 3-PP-InsP) showed no immediate effect. Furthermore, uncaging of 1,5-(PP)-InsP but not 3,5-(PP)-InsP 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)-InsP impacts β-cell activity by regulating granule localization and/or priming and calcium signaling in concert.