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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
Author(s) -
Wilcox Robert A.,
Whitham Emma.M.,
Liu Changsheng,
Potter Barry V.L.,
Nahorski Stefan R.
Publication year - 1993
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(93)80817-e
Subject(s) - inositol , chemistry , phosphatase , agonist , inositol phosphate , receptor , intracellular , calcium , inositol trisphosphate , stereochemistry , biochemistry , endocrinology , medicine , biology , enzyme , organic chemistry
Myo ‐inositol 1,3,4,5‐tetrakisphosphate [Ins(1,3,4,5)P 4 ] acts as a full agonist for Ca 2+ release in saponin‐permeabilised SH‐SY5Y neuroblastoma cells. Studies were conducted in the presence of myo ‐inositol hexakisphosphate (InsP 6 , 10 μM), to inhibit the Ins(1,3,4,5)P 4 ‐3‐phosphatase catalysed back conversion of Ins(1,3,4,5)P 4 to Ins(1,4,5)P 3 . HPLC analysis confirmed that Ins(1,3,4,5)P 4 releases the entire content of Ins(1,4,5)P 3 ‐sensitive intracellular Ca 2+ 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)P 4 analogue. DL‐Ins(1,3,4,5)P 4 ‐3S specifically displaced [ 3 H]Ins(1,4,5)P 3 from bovine adrenal cortex Ins(1,4,5)P 3 binding sites (IC 50 = 889 nM, compared to Ins(1,4,5)P 3 ,1C 50 = 4.4 nM and Ins(1,3,4,5)P 4 , IC 50 = 152 nM). dl ‐Ins(1,3,4,5)P 4 ‐3S was a full agonist for Ca 2+ release (EC 50 = 4.7 μM), being 90‐ and 2‐fold less potent than Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 (with InsP 6 ), 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)P 4 second messenger functions, since its resistance to 3‐phosphatase action precludes the inconvenient artefact of steady state Ins(1,4,5)P 3 generation.