AI Article Synopsis
- Inositol pyrophosphates are complex signaling molecules that play a key role in glucose uptake and insulin sensitivity, but the specific functions of inositol octaphosphates remain largely unknown.
- Researchers developed two versions of these molecules that can enter cells and be activated by light, allowing them to study their effects on living β-cells.
- The activation of one specific isomer, 1,5-(PP)-InsP, significantly reduced calcium oscillations inside the cells and influenced the movement of granuphilin, a protein crucial for the secretion of vesicles, suggesting a pivotal role in regulating β-cell function.
Article 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-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.
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| http://dx.doi.org/10.1021/jacs.0c01697 | DOI Listing |
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