TY - JOUR
T1 - 3-Position modification of myo-inositol 1,4,5-trisphosphate
T2 - consequences for intracellular Ca2+ mobilisation and enzyme recognition
AU - Safrany, Stephen T.
AU - Wilcox, Robert A.
AU - Liu, Changsheng
AU - Potter, Barry V.L.
AU - Nahorski, Stefan R.
PY - 1992/7/1
Y1 - 1992/7/1
N2 - The ability of the novel D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) analogues, L-chiro-inositol 2,3,5-trisphosphate (L-ch-Ins(2,3,5)P3) and D-3-deoxy-3-fluoro-myo-inositol 1,4,5-trisphophate (3F-Ins(1,4,5)P3), to bind to the Ins(1,4,5)P3 receptor, mobilise intracellular Ca2+ stores and interact with metabolic enzymes has been investigated. L-ch-Ins(2,3,5)P3 and 3F-Ins(1,4,5)P3 were bound by the Ins(1,4,5)P3 receptor from bovine adrenal cortex with relatively high affinity (Ki values 60.4 and 8.0 nM respectively) but with lower affinity than Ins(1,4,5)P3 (KD = 5.9 nM). Both analogues were apparent full agonists at the Ca2+ mobilising receptor in SH-SY5Y cells, but were less potent than Ins(1,4,5)P3 (EC50 L-ch-Ins(2,3,5)P3 = 1.4 μM,F-Ins(1,4,5)P3 = 0.37 μM and Ins(1,4,5)P3 = 0.12 μM). L-ch-Ins(2,3,5)P3 and 3F-Ins(1,4,5)P3 were resistant to Ins(1,4,5)P3 3-kinase, and were potent inhibitors of the enzyme (Ki values 7.1 and 8.6 μM respectively). 3F-Ins(1,4,5)P3 was hydrolysed by Ins(1,4,5)P3 5-phosphatase at a similar rate to Ins(1,4,5)P3, but inhibited dephosphorylation of [3H]Ins(1,4,5)P3 with high potency (apparent Ki = 3.9 μM) L-ch-Ins(2,3,5)P3 was also recognised by the enzyme with high affinity (Ki = 7.7 μM) but was resistant to hydrolysis. These results suggest that the environment around C-3 is of major importance for recognition not only by Ins(1,4,5)P3 3-kinase but also by Ins(1,4,5)P3 5-phosphatase.
AB - The ability of the novel D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) analogues, L-chiro-inositol 2,3,5-trisphosphate (L-ch-Ins(2,3,5)P3) and D-3-deoxy-3-fluoro-myo-inositol 1,4,5-trisphophate (3F-Ins(1,4,5)P3), to bind to the Ins(1,4,5)P3 receptor, mobilise intracellular Ca2+ stores and interact with metabolic enzymes has been investigated. L-ch-Ins(2,3,5)P3 and 3F-Ins(1,4,5)P3 were bound by the Ins(1,4,5)P3 receptor from bovine adrenal cortex with relatively high affinity (Ki values 60.4 and 8.0 nM respectively) but with lower affinity than Ins(1,4,5)P3 (KD = 5.9 nM). Both analogues were apparent full agonists at the Ca2+ mobilising receptor in SH-SY5Y cells, but were less potent than Ins(1,4,5)P3 (EC50 L-ch-Ins(2,3,5)P3 = 1.4 μM,F-Ins(1,4,5)P3 = 0.37 μM and Ins(1,4,5)P3 = 0.12 μM). L-ch-Ins(2,3,5)P3 and 3F-Ins(1,4,5)P3 were resistant to Ins(1,4,5)P3 3-kinase, and were potent inhibitors of the enzyme (Ki values 7.1 and 8.6 μM respectively). 3F-Ins(1,4,5)P3 was hydrolysed by Ins(1,4,5)P3 5-phosphatase at a similar rate to Ins(1,4,5)P3, but inhibited dephosphorylation of [3H]Ins(1,4,5)P3 with high potency (apparent Ki = 3.9 μM) L-ch-Ins(2,3,5)P3 was also recognised by the enzyme with high affinity (Ki = 7.7 μM) but was resistant to hydrolysis. These results suggest that the environment around C-3 is of major importance for recognition not only by Ins(1,4,5)P3 3-kinase but also by Ins(1,4,5)P3 5-phosphatase.
KW - Ca mobilization
KW - Inositol phosphate analogues
KW - Second messenger
UR - http://www.scopus.com/inward/record.url?scp=0026780170&partnerID=8YFLogxK
U2 - 10.1016/0922-4106(92)90071-3
DO - 10.1016/0922-4106(92)90071-3
M3 - Article
C2 - 1330634
AN - SCOPUS:0026780170
VL - 226
SP - 265
EP - 272
JO - European Journal of Pharmacology: Molecular Pharmacology
JF - European Journal of Pharmacology: Molecular Pharmacology
SN - 0922-4106
IS - 3
ER -