Binding and activity of the nine possible regioisomers of myo-inositol tetrakisphosphate at the inositol 1,4,5-trisphosphate receptor

Neil T. Burford, Stefan R. Nahorski, Sung Kee Chung, Young Tae Chang, Robert A. Wilcox

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

All 9 racemic regiosomers (15 enantiomerically) of myo-inositol tetrakisphosphates (IP4s): DL-Ins(1,2,4,5)P4 [A], DL-Ins(1,2,4,6)P4 [B], Ins(1,2,3,5)P4 [C], Ins(1,3,4,6)P4 [D], Ins(2,4,5,6)P4 [E], DL-Ins(1,3,4,5)P4 [F], DL-Ins(1,2,5,6)P4 [G], DL-Ins(1,2,3,4)P4 [H] and DL-Ins(1,4,5,6)P4 [I] were investigated for their ability to bind to the D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor in bovine adrenal cortical membranes, and for their ability to mobilize 45Ca2+ from Ins(l,4,5)P3-sensitive Ca2+ stores in permeabilized Chinese hamster ovary (CHO) cells. DL-Ins(1,2,4,5)P4 (K1 = 11 nM) bound to Ins(1,4,5)P3 receptors with an affinity only 2-fold lower than Ins(1,4,5)P3 (K1 = 6 nM), Ins(1,2,3,5)P4, Ins(1,3,4,6)P4, Ins(2,4,5,6)P4, DL-Ins(1,3,4,5)P4, DL-Ins(1,2,3,4)P4 and DL-Ins(1,4,5,6)P4 bound with affinities of between 0.4 - 0.7 μM. DL-Ins(1,2,4,6)P4 and DL-Ins(1,2,5,6)P4 bound to the Ins(1,4,5)P3 receptor with low affinity (approximately 2-3 μM). All but one of the IP4s mediated release of 45Ca2+ from stores of permeabilized CHO cells with a similar rank order of potency as that for Ins(1,4,5)P3 receptor binding, being between 16-fold and 50-fold less potent at releasing 45Ca2+ compared with their apparent binding affinities to the Ins(1,4,5)P3 receptor. The notable exception was Ins(1,2,3,5)P4, which showed an approximately 200-fold lower potency compared with its affinity for the Ins(1,4,5)P3 receptor. Ins(1,2,3,5)P4 may be a useful lead compound for the rational design of novel synthetic Ins(1,4,5)P3 analogues possessing structure-activity profiles with relatively high binding affinity, but low intrinsic efficacy, and hence partial agonists and antagonists at the Ins(1,4,5)P3 receptor.

Original languageEnglish
Pages (from-to)301-310
Number of pages10
JournalCell Calcium
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 1997
Externally publishedYes

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