title: Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo.
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.
authors: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors: Igor
authors: I
authors: Pavlovic
authors: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors: Divyeshsinh T
authors: DT
authors: Thakor
authors: Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305, USA.
authors: Jessica R
authors: JR
authors: Vargas
authors: Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305, USA.
authors: Colin J
authors: CJ
authors: McKinlay
authors: European Molecular Biology Laboratory (EMBL), Cell Biology &Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Hauke
authors: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors: Philipp
authors: P
authors: Anstaett
authors: Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga, Malaga 29071, Spain.
authors: Rafael C
authors: RC
authors: Camuña
authors: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors: Laurent
authors: L
authors: Bigler
authors: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.
authors: Gilles
authors: G
authors: Gasser
authors: European Molecular Biology Laboratory (EMBL), Cell Biology &Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Carsten
authors: C
authors: Schultz
authors: Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305, USA.
authors: Paul A
authors: PA
authors: Wender
authors: Department of Chemistry and Pharmacy, Albert-Ludwigs University Freiburg, Albertstrasse 21, 79104 Freiburg, Germany.
authors: Henning J
authors: HJ
authors: Jessen
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007295:Inositol Phosphates / Q000138:chemical synthesis / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D053758:Nanoparticles; D049329:Nanostructures; D055668:Photochemical Processes; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D007295:Inositol Phosphates; C402123:inositol heptakisphosphate; D051057:Proto-Oncogene Proteins c-akt