The Synthesis of Membrane Permeant Derivatives of myo-Inositol 1,4,5-Trisphosphate

Stuart J. Conway; Jan W. Thuring; Sylvain Andreu; Brynn T. Kvinlaug; H. Llewelyn Roderick; Martin D. Bootman; Andrew B. Holmes

doi:10.1071/CH06357

RESEARCH ARTICLE

The Synthesis of Membrane Permeant Derivatives of myo-Inositol 1,4,5-Trisphosphate

Stuart J. Conway ^A ^B ^G , Jan W. Thuring ^A , Sylvain Andreu ^A , Brynn T. Kvinlaug ^C , H. Llewelyn Roderick ^C ^D , Martin D. Bootman ^C and Andrew B. Holmes ^E ^F ^G

+ Author Affiliations

- Author Affiliations

^A Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.

^B School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife KY16 9ST, UK.

^C Laboratory of Molecular Signalling, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.

^D Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.

^E School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne VIC 3010, Australia.

^F Department of Chemistry, Imperial College London, London SW7 2AZ, UK.

^G Corresponding authors. Email: sjc16@st-andrews.ac.uk; aholmes@unimelb.edu.au

Australian Journal of Chemistry 59(12) 887-893 https://doi.org/10.1071/CH06357
Submitted: 4 October 2006 Accepted: 28 October 2006 Published: 20 December 2006

Abstract

In order to enable the study of the intracellular second messenger d-myo-inositol 1,4,5-trisphosphate (InsP₃) and its receptors (InsP₃Rs), it has been desirable to develop protected derivatives of InsP₃ that are able to enter the cell, upon extracellular application. The subsequent removal of the lipophilic protecting groups, by intracellular enzymes, releases InsP₃ and leads to the activation of InsP₃Rs. Two syntheses of d-myo-inositol 1,4,5-trisphosphate hexakis(butyryloxymethyl) ester (d-InsP₃/BM) and one of l-InsP₃/BM are reported. It is demonstrated that extracellular application of the d-enantiomer results in Ca²⁺ release, which is thought to occur via InsP₃Rs. Application of the l-enantiomer resulted in little Ca²⁺ release.

Acknowledgments

The authors gratefully acknowledge funding from the Biotechnology and Biological Sciences Research Council and thank the Engineering and Physical Sciences Research Council Mass Spectrometry service, Swansea. S.J.C. thanks Hughes Hall, Cambridge, for a Research Fellowship. B.T.K. thanks the Newton Trust for funding. H.L.R. thanks the Royal Society for a Research Fellowship. A.B.H. acknowledges generous support from the Australian Research Council, the Commonwealth Scientific and Industrial Research Organisation, the Victorian Endowment for Science, Knowledge and Innovation, and the University of Melbourne.

References

The Synthesis of Membrane Permeant Derivatives of myo-Inositol 1,4,5-Trisphosphate

Abstract

Acknowledgments

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