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. Camunã, Laurent Bigler, Gilles Gasser, Carsten Schultz, Paul A. Wender, Henning J. Jessen

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Article number10622
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 4 2016
Externally publishedYes

Fingerprint

inositols
Inositol
homeostasis
delivery
glucose
cells
transporter
insulin
secretions
cytoplasm
synthesis
molecules
indication
analogs
Homeostasis
membranes
modulation
nanoparticles
irradiation
Glucose

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Pavlovic, I., Thakor, D. T., Vargas, J. R., McKinlay, C. J., Hauke, S., Anstaett, P., ... Jessen, H. J. (2016). Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Nature Communications, 7, [10622]. https://doi.org/10.1038/ncomms10622

Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. / Pavlovic, Igor; Thakor, Divyeshsinh T.; Vargas, Jessica R.; McKinlay, Colin J.; Hauke, Sebastian; Anstaett, Philipp; Camunã, Rafael C.; Bigler, Laurent; Gasser, Gilles; Schultz, Carsten; Wender, Paul A.; Jessen, Henning J.

In: Nature Communications, Vol. 7, 10622, 04.02.2016.

Research output: Contribution to journalArticle

Pavlovic, I, Thakor, DT, Vargas, JR, McKinlay, CJ, Hauke, S, Anstaett, P, Camunã, RC, Bigler, L, Gasser, G, Schultz, C, Wender, PA & Jessen, HJ 2016, 'Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo', Nature Communications, vol. 7, 10622. https://doi.org/10.1038/ncomms10622
Pavlovic, Igor ; Thakor, Divyeshsinh T. ; Vargas, Jessica R. ; McKinlay, Colin J. ; Hauke, Sebastian ; Anstaett, Philipp ; Camunã, Rafael C. ; Bigler, Laurent ; Gasser, Gilles ; Schultz, Carsten ; Wender, Paul A. ; Jessen, Henning J. / Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. In: Nature Communications. 2016 ; Vol. 7.
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