TY - JOUR
T1 - Photolysis of Caged Inositol Pyrophosphate InsP8Directly Modulates Intracellular Ca2+Oscillations and Controls C2AB Domain Localization
AU - Bittner, Tamara
AU - Wittwer, Christopher
AU - Hauke, Sebastian
AU - Wohlwend, Daniel
AU - Mundinger, Stephan
AU - Dutta, Amit K.
AU - Bezold, Dominik
AU - Dürr, Tobias
AU - Friedrich, Thorsten
AU - Schultz, Carsten
AU - Schultz, Carsten
AU - Jessen, Henning J.
AU - Jessen, Henning J.
AU - Jessen, Henning J.
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/6/17
Y1 - 2020/6/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086626104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086626104&partnerID=8YFLogxK
U2 - 10.1021/jacs.0c01697
DO - 10.1021/jacs.0c01697
M3 - Article
C2 - 32459478
AN - SCOPUS:85086626104
SN - 0002-7863
VL - 142
SP - 10606
EP - 10611
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 24
ER -