Modification at C2 of myo-inositol 1,4,5-trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities.
Modification at C2 of myo-inositol 1,4,5-trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities.
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肌醇 1,4,5-三磷酸 C2 处的修饰产生具有有效生物活性的肌醇三磷酸和四磷酸。
DOI：
10.1111/j.1432-1033.1994.tb18972.x
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
B. Potter
中科院分区：
文献类型：
--
作者：
R. A. Wilcox;S. Safrany;D. Lampe;S. J. Mills;S. Nahorski;B. Potter
小说2-position-modified D-myo-inositol 1 4 5-trisphosphate (Ins(1、4、5)P3)类似物,DL-2-deoxy-2-fluoro-myo-inositol 1, 4, 5-trisphosphate [DL-2F-Ins(1、4、5)P3], DL-myo-inositol 1, 2, 4, 5-tetrakisphosphate [DL-Ins(1、2、4、5)P4), DL-scyllo-inositol 1, 2, 4-trisphosphate [DL-sc-Ins(1、2、4)P3], scyllo-inositol 1, 2, 4, 5-tetrakisphosphate [sc-Ins(1、2、4、5)P4)和scyllo-inositol 1, 2, 4, 5-tetrakisphosphorothioate [sc-Ins(1、2、4、5)PS4]了绑定到Ins的能力(1、4、5)P3受体,调动细胞内Ca2+储存并与代谢酶相互作用。除了sc-Ins(1,2,4,5)PS4外，所有Ins(1,4,5)P3类似物都能从牛肾上腺皮质的受体中取代[3H]Ins(1,4,5)P3，并且是SH-SY5Y细胞Ca2+动员Ins(1,4,5)P3受体的明显有效的完全激动剂，其IC50和EC50值分别为：sc-Ins(1,2,4,5)P4 (IC50 14 nM, EC50 77 nM), DL-2F-Ins(1,4,5)P3 (IC50 25 nM, EC50 105 nM), DL-Ins(1,2,4,5)P4 (IC50 26 nM, EC50 163 nM), DL-sc-Ins(1,2,4)P3 （IC50 52 nM, EC50 171 nM）与Ins(1,4,5)P3 （IC50 4 nM, EC50 52 nM）相比。sc-Ins(1,2,4,5)P4与Ins(1,4,5)P3具有同等的Ca2+释放能力，使其成为最有效的四分磷酸肌醇，确实是Ins(1,4,5)P3的类似物。相比之下，尽管sc-Ins(1,2,4,5)P4 （IC50 425 nM, EC50 1603 nM）是一种明显弱于Ins(1,4,5)P3的配体和激动剂，但它是一种具有高内在活性的部分激动剂，其最大有效浓度仅释放约80%的SH-SY5Y细胞中Ins(1,4,5)P3敏感的Ca2+储存。Ins(1,4,5)P3和sc-Ins(1,2,4,5)P4容易被Ins(1,4,5)P3的3-激酶和5-磷酸酶活性代谢，DL-2F-Ins(1,4,5)P3和DL-sc-Ins(1,2,4)P3对5-磷酸酶有抗性，而sc-Ins(1,2,4,5)PS4和DL-Ins(1,2,4,5)P4对3-激酶和5-磷酸酶活性都有抗性，并且是5-磷酸酶的有效抑制剂（Ki分别为300 nM和2.9微米）。这些结果表明，修改Ins(1,4,5)P3的2位，即使是阴离子基团，也不会严重影响Ins(1,4,5)P3的结合相互作用或Ca2+释放，这表明Ins(1,4,5)P3的2-OH不能与其受体的结合位点显著相互作用。然而，远离关键的邻区4,5-二磷酸的修饰会影响类似物在Ca2+释放中的功效。
Novel 2-position-modified D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] analogues, DL-2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate [DL-2F-Ins(1,4,5)P3], DL-myo-inositol 1,2,4,5-tetrakisphosphate [DL-Ins(1,2,4,5)P4], DL-scyllo-inositol 1,2,4-trisphosphate [DL-sc-Ins(1,2,4)P3], scyllo-inositol 1,2,4,5-tetrakisphosphate [sc-Ins(1,2,4,5)P4] and scyllo-inositol 1,2,4,5-tetrakisphosphorothioate [sc-Ins(1,2,4,5)PS4] were investigated for their ability to bind to the Ins(1,4,5)P3 receptor, mobilise intracellular Ca2+ stores and interact with metabolic enzymes. With the exception of sc-Ins(1,2,4,5)PS4, all the Ins(1,4,5)P3 analogues potently displaced [3H]Ins(1,4,5)P3 from its receptor in bovine adrenal cortex and were apparently potent full agonists at the Ca2+ mobilising Ins(1,4,5)P3 receptor of SH-SY5Y cells, giving respective IC50 and EC50 values of: sc-Ins(1,2,4,5)P4 (IC50 14 nM, EC50 77 nM), DL-2F-Ins(1,4,5)P3 (IC50 25 nM, EC50 105 nM), DL-Ins(1,2,4,5)P4 (IC50 26 nM, EC50 163 nM), DL-sc-Ins(1,2,4)P3 (IC50 52 nM, EC50 171 nM), compared to Ins(1,4,5)P3 (IC50 4 nM, EC50 52 nM). sc-Ins(1,2,4,5)P4 was equipotent to Ins(1,4,5)P3 for Ca2+ release making it the most potent inositol tetrakisphosphate and indeed Ins(1,4,5)P3 analogue yet characterised. In contrast, although sc-Ins(1,2,4,5)P4 (IC50 425 nM, EC50 1603 nM) was a significantly weaker ligand and agonist than Ins(1,4,5)P3, it was a partial agonist of high intrinsic activity with maximally effective concentrations releasing only about 80% of Ins(1,4,5)P3-sensitive Ca2+ stores of SH-SY5Y cells. Ins(1,4,5)P3 and sc-Ins(1,2,4,5)P4 were readily metabolised by Ins(1,4,5)P3 3-kinase and 5-phosphatase activities, DL-2F-Ins(1,4,5)P3 and DL-sc-Ins(1,2,4)P3 were resistant to 5-phosphatase, while sc-Ins(1,2,4,5)PS4 and DL-Ins(1,2,4,5)P4 were resistant to both 3-kinase and 5-phosphatase activity and were potent inhibitors of the 5-phosphatase enzyme (Ki = 300 nM and 2.9 microM, respectively). These results demonstrate that modification of the 2-position of Ins(1,4,5)P3, even with an anionic group, does not critically affect Ins(1,4,5)P3 binding interaction or Ca2+ release, suggesting that the 2-OH of Ins(1,4,5)P3 fails to interact significantly with the binding site of its receptor. However, modification remote from the crucial vicinal 4,5-bisphosphate can affect analogue efficacy in Ca2+ release.
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影响因子：
56.9
作者：
FINCH, EA;TURNER, TJ;GOLDIN, SM
通讯作者：
GOLDIN, SM
DOI：
10.1073/pnas.88.7.2951
发表时间：
1991-04-01
影响因子：
11.1
作者：
DANOFF, SK;FERRIS, CD;ROSS, CA
通讯作者：
ROSS, CA
影响因子：
11.4
作者：
SUDHOF, TC;NEWTON, CL;MIGNERY, GA
通讯作者：
MIGNERY, GA
大鼠肌醇 1,4,5-三磷酸受体的结构和表达。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mignery,GA;Newton,CL;Archer3rd,BT;Südhof,TC
通讯作者：
Südhof,TC
激素诱发的细胞内钙释放是一个量子过程。
DOI：
--
发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Muallem,S;Pandol,SJ;Beeker,TG
通讯作者：
Beeker,TG