The Novel Ins(1,4,5)P₃ Analog 3-Amino-3-deoxy-Ins(1,4,5)P₃: A pH-Dependent Ins(1,4,5)P₃ Receptor Partial Agonist in SH-SY5Y Neuroblastoma Cells

We have synthesized the first amino-substituted inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] analogue, d-3-amino-3-deoxy-myo-Ins(1,4,5)P₃ (9). Although 9 is a full agonist at the Ca²⁺ mobilizing Ins(1,4,5)P₃ receptor at pH 7.2 and 7.6, it is apparently a high intrinsic activity partial agonist at pH 6.8, releasing only 80% of the Ins(1,4,5)P₃-sensitive Ca²⁺ stores of SH-SY5Y cells. Additionally, 9 was able to fully displace [³H]Ins(1,4,5)P₃ from binding sites in rat cerebellum membranes at both pH 6.8 and 7.6, indicating a full interaction with the Ins(1,4,5)P₃ receptor. The activity displayed by this amino analogue is unexpected and may be indicative of a pH-dependent conformational change in the amino acid residues comprising the Ins(1,4,5)P₃ binding site.