The behaviour of myo-inositol hexakisphosphate in the presence of magnesium(II) and calcium(II): Protein-free soluble InsP(6) is limited to 49 μM under cytosolic/nuclear conditions

Progress in the biology of myo-inositol hexakisphosphate (InsP(6)) has been delayed by the lack of a quantitative description of its multiple interactions with divalent cations. Our recent initial description of these [J. Torres, S. Dominguez, M.F. Cerda, G. Obal, A. Mederos, R.F. Irvine, A. Diaz, C. Kremer, J. Inorg. Biochem. 99 (2005) 828–840] predicted that under cytosolic/nuclear conditions, protein-free soluble InsP(6) occurs as Mg(5)(H(2)L), a neutral complex that exists thanks to a significant, but undefined, window of solubility displayed by solid Mg(5)(H(2)L) · 22H(2)O (L is fully deprotonated InsP(6)). Here we complete the description of the InsP(6)–Mg(2+)–Ca(2+) system, defining the solubilities of the Mg(2+) and Ca(2+) (Ca(5)(H(2)L) · 16H(2)O) solids in terms of K(s0) = [M(2+)](5)[H(2)L(10−)], with pK(s0) = 32.93 for M = Mg and pK(s0) = 39.3 for M = Ca. The concentration of soluble Mg(5)(H(2)L) at 37 °C and I = 0.15 M NaClO(4) is limited to 49 μM, yet InsP(6) in mammalian cells may reach 100 μM. Any cytosolic/nuclear InsP(6) in excess of 49 μM must be protein- or membrane-bound, or as solid Mg(5)(H(2)L) · 22H(2)O, and any extracellular InsP(6) (e.g. in plasma) is surely protein-bound.