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Myo-inositol 1,3,4,5-tetrakisphosphate can independently mobilise intracellular calcium, via the inositol 1,4,5-trisphosphate receptor: studies with myo-inositol 1,4,5-trisphosphate-3-phosphorothioate and myo-inositol hexakisphosphate.

Abstract
Myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] acts as a full agonist for Ca2+ release in saponin-permeabilised SH-SY5Y neuroblastoma cells. Studies were conducted in the presence of myo-inositol hexakisphosphate (InsP6, 10 microM), to inhibit the Ins(1,3,4,5)P(4)-3-phosphatase catalysed back conversion of Ins(1,3,4,5)P4 to Ins(1,4,5)P3. HPLC analysis confirmed that Ins(1,3,4,5)P4 releases the entire content of Ins(1,4,5)P3-sensitive intracellular Ca2+ stores, independent of 3-phosphatase activity. Further we utilised racemic myo-inositol 1,4,5-trisphosphate-3-phosphorothioate [DL-Ins(1,3,4,5)P(4)-3S], a novel intrinsically Ins(1,3,4,5)P(4)-3-phosphatase resistant Ins(1,3,4,5)P4 analogue. DL-Ins(1,3,4,5)P(4)-3S specifically displaced [3H]Ins(1,4,5)P3 from bovine adrenal cortex Ins(1,4,5)P3 binding sites (IC50 = 889 nM, compared to Ins(1,4,5)P3, IC50 = 4.4 nM and Ins(1,3,4,5)P4, IC50 = 152 nM). DL-Ins(1,3,4,5)P(4)-3S was a full agonist for Ca2+ release (EC50 = 4.7 microM), being 90- and 2-fold less potent than Ins(1,4,5)P3 and Ins(1,3,4,5)P4 (with InsP6), respectively. DL-Ins(1,3,4,5)P(4)-3S will be an important tool for identification of potentially exclusive Ins(1,3,4,5)P4 second messenger functions, since its resistance to 3-phosphatase action precludes the inconvenient artefact of steady state Ins(1,4,5)P3 generation.
AuthorsR A Wilcox, E M Whitham, C Liu, B V Potter, S R Nahorski
JournalFEBS letters (FEBS Lett) Vol. 336 Issue 2 Pg. 267-71 (Dec 27 1993) ISSN: 0014-5793 [Print] England
PMID8262243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Calcium Channels
  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol Phosphates
  • Organothiophosphorus Compounds
  • Receptors, Cytoplasmic and Nuclear
  • inositol-1,3,4,5-tetrakisphosphate
  • inositol 1,4,5-triphosphorothioate
  • Phytic Acid
  • Inositol 1,4,5-Trisphosphate
  • Calcium
Topics
  • Animals
  • Binding Sites
  • Calcium (metabolism)
  • Calcium Channels (drug effects, metabolism)
  • Cattle
  • Chromatography, High Pressure Liquid
  • Humans
  • Inositol 1,4,5-Trisphosphate (analogs & derivatives)
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol Phosphates (pharmacology)
  • Organothiophosphorus Compounds (pharmacology)
  • Phytic Acid (pharmacology)
  • Receptors, Cytoplasmic and Nuclear (drug effects, metabolism)
  • Tumor Cells, Cultured

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