Ca2+‐mobilising properties of synthetic fluoro‐analogues of myo‐inositol 1,4,5‐trisphosphate and their interaction with myo‐inositol 1,4,5‐trisphosphate 3‐kinase and 5‐phosphatase

摘要

>The ability of two fluoro-analogues of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) to mobilize intracellular Ca2+ stores in SH-SY5Y neuroblastoma cells has been investigated. DL-2-deoxy-2-fluoro-scyllo-Ins(1,4,5)P₃ (2F-Ins(1,4,5)P₃) and DL-2,2-difluoro-2-deoxy-myo-Ins(1,4,5)P₃ (2,2-F₂-Ins(1,4,5)P₃) were full agonists (EC₅₀s 0.77 and 0.41 μM respectively) and slightly less potent than D-Ins(1,4,5)P₃ (EC₅₀ 0.13 μM), indicating that the axial 2-hydroxyl group of Ins(1,4,5)P₃ is relatively unimportant in receptor binding and stimulation of Ca2+ release. Both analogues mobilized Ca2+ with broadly similar kinetics and were substrates for Ins(1,4,5)P₃ 3-kinase but, qualitatively, were slightly poorer than Ins(1,4,5)P₃. 2F-Ins(1,4,5)P₃ was a weak substrate for Ins(1,4,5)P₃ 5-phosphatase but 2,2-F₂-Ins(1,4,5)P₃ was apparently not hydrolysed by this enzyme, although it inhibited its activity potently (K_i = 26 μM).