Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo

Igor Pavlovic, Divyeshsinh T. Thakor, Jessica R. Vargas, Colin J. McKinlay, Sebastian Hauke, Philipp Anstaett, Rafael C. Camuña, Laurent Bigler, Gilles Gasser, Carsten Schultz, Paul A. Wender () and Henning J. Jessen ()
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Igor Pavlovic: University of Zurich
Divyeshsinh T. Thakor: University of Zurich
Jessica R. Vargas: Stanford University
Colin J. McKinlay: Stanford University
Sebastian Hauke: European Molecular Biology Laboratory (EMBL), Cell Biology & Biophysics Unit
Philipp Anstaett: University of Zurich
Rafael C. Camuña: Facultad de Ciencias, Universidad de Málaga
Laurent Bigler: University of Zurich
Gilles Gasser: University of Zurich
Carsten Schultz: European Molecular Biology Laboratory (EMBL), Cell Biology & Biophysics Unit
Paul A. Wender: Stanford University
Henning J. Jessen: Albert-Ludwigs University Freiburg

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: Abstract Inositol pyrophosphates, such as diphospho-myo-inositol pentakisphosphates (InsP7), are an important family of signalling molecules, implicated in many cellular processes and therapeutic indications including insulin secretion, glucose homeostasis and weight gain. To understand their cellular functions, chemical tools such as photocaged analogues for their real-time modulation in cells are required. Here we describe a concise, modular synthesis of InsP7 and caged InsP7. The caged molecule is stable and releases InsP7 only on irradiation. While photocaged InsP7 does not enter cells, its cellular uptake is achieved using nanoparticles formed by association with a guanidinium-rich molecular transporter. This novel synthesis and unprecedented polyphosphate delivery strategy enable the first studies required to understand InsP7 signalling in cells with controlled spatiotemporal resolution. It is shown herein that cytoplasmic photouncaging of InsP7 leads to translocation of the PH-domain of Akt, an important signalling-node kinase involved in glucose homeostasis, from the membrane into the cytoplasm.

Date: 2016
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DOI: 10.1038/ncomms10622

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