Solution behaviour of myo-inositol hexakisphosphate in the presence of multivalent cations. Prediction of a neutral pentamagnesium species under cytosolic/nuclear conditions

myo-Inositol hexakisphosphate (Ins P 6) is an ubiquitous and abundant molecule in the cytosol and nucleus of eukaryotic cells whose biological functions are incompletely known. A major hurdle for studying the biology of Ins P 6 has been a deficiency of a full understanding of the chemistry of its interaction with divalent and trivalent cations. This deficiency has limited our appreciation of how it remains in solution within cells, and the likely degree to which it might interact in vivo with physiologically important cations such as Ca 2+ and Fe 3+. We report here the initial part of the description of the Ins P 6-multivalent cation chemistry, including its solution equilibria studied by high resolution potentiometry and (for the Fe(III)/Fe(II) couple) cyclic voltammetry. Ins P 6 forms anionic complexes of high affinities and 1:1 stoichiometry with Mg(II), Ca(II), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II). Of particular importance is the observation that, in the exceptional case of Mg(II), Ins P 6 forms the species [Mg 5(H 2L)] (L representing fully deprotonated Ins P 6); this soluble neutral species is predicted to be the predominant form of Ins P 6 under nuclear or cytosolic conditions in animal cells. Contrary to previous suggestions, Ins P 6 is predicted not to interact with cytosolic calcium even when calcium is increased during signalling events. In vitro, Ins P 6 also forms high affinity 1:1 complexes with Fe(III) and Al(III). However, our data predict that in the biological context of excess free Mg(II), neither Fe(III) nor Fe(II) are complexed by Ins P 6.