2ND MESSENGER SPECIFICITY OF THE INOSITOL TRISPHOSPHATE RECEPTOR - REAPPRAISAL BASED ON NOVEL INOSITOL PHOSPHATES

To further understand how the second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] interacts with its intracellular receptor, we injected 47 highly purified inositol phosphate (InsP) positional isomers in Xenopus oocytes and compared their potency in releasing intracellular Ca2+. The potency of the Ca2+-releasing InsPs spanned four orders of magnitude. Seven compounds, including the novel inositol 1,2,4,5-tetrakisphosphate [D/L-Ins(1,2,4,5)P-4] and D/L-Ins(1,4,6)P-3, had a very high potency. All of these highly active InsPs shared the following structure: two D-trans-equatorial phosphates (eq-P) and one equatorial hydroxyl leg-OH) attached to ring carbons D-4, D-5, and D-6 (or to the structurally equivalent D-1, D-6, and D-5 carbons). This permissive structure was not sufficient for Ca2+ release, because it was also found in two inactive compounds, Ins(1,6!Pz and Ins(1,3,6)P-3. To be active, InsPs also required the structural equivalent of a D-3 eq-OH and/or a D-1 eq-P. Together, our data reveal how the structure of the InsP molecule affects its ability to release Ca2+.