THE NOVEL INS(1,4,5)P-3 ANALOG 3-AMINO-3-DEOXY-INS(1,4,5)P-3 - A PH-DEPENDENT INS(1,4,5)P-3 RECEPTOR PARTIAL AGONIST IN SH-SY5Y NEUROBLASTOMA-CELLS

We have synthesized the first amino-substituted inositol 1,4,5-trispho sphate [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 rec eptor at pH 7.2 and 7.6, it is apparently a high intrinsic activity pa rtial agonist at pH 6.8, releasing only 80% of the Ins(1,4,5)P3-sensit ive Ca2+ stores of SH-SY5Y cells. Additionally, 9 was able to fully di splace [H-3]Ins(1,4,5)P3 from binding sites in rat cerebellum membrane s 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 une xpected and may be indicative of a pH-dependent conformational change in the amino acid residues comprising the Ins(1,4,5)P3 binding site.