A WORTMANNIN-SENSITIVE PHOSPHATIDYLINOSITOL 4-KINASE THAT REGULATES HORMONE-SENSITIVE POOLS OF INOSITOLPHOSPHOLIPIDS
A WORTMANNIN-SENSITIVE PHOSPHATIDYLINOSITOL 4-KINASE THAT REGULATES HORMONE-SENSITIVE POOLS OF INOSITOLPHOSPHOLIPIDS
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DOI：
10.1073/pnas.92.12.5317
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发表时间：
1995-06-06
影响因子：
11.1
通讯作者：
BALLA, T
中科院分区：
文献类型：
--
作者：
NAKANISHI, S;CATT, KJ;BALLA, T
磷脂酰肌醇4，5-二磷酸[PtdIns(4)P-2]的合成是由钙激活激素和生长因子产生的细胞内信号的直接前体，由磷脂酰肌醇4-激酶(PtdIns 4-Kinase)将磷脂酰肌醇转化为磷脂酰肌醇4-磷酸[PtdIns(4)P]，尽管细胞中含有几种PtdIns 4-激酶，但负责调节激素敏感的PtdIns(4，5)P-2池合成的酶尚未确定。在本报告中，我们描述了微摩尔浓度的Wortmannin(WT)对完整的肾上腺小球细胞合成激素敏感的PtdIns(4)P和PtdIns(4，5)P-2池的抑制作用，以及肾上腺皮质提取物中存在WT敏感的PtdIns 4-激酶，除了它对PtdIns 3激酶抑制剂WT的敏感性外，这种酶与公认的膜结合的PtdIns 4-激酶的不同之处在于它的分子大小和弱的膜结合，WT抑制这种PtdIns 4激酶导致血管紧张素II刺激的肾小球细胞中激素敏感的PtdIns(4，5)PZ池的迅速丧失，从而导致血管紧张素II刺激的肾小球细胞中激素敏感的PtdIns(4，5)Pz池的迅速丧失WT治疗抑制了各种激动剂刺激的细胞，包括肾上腺肾小球细胞、NIH 3T3成纤维细胞和Jurkat淋巴母细胞的肌醇1，4，5三磷酸和胞浆[Ca+]的持续增加，但不是最初的增加。这些结果表明，在几种细胞类型中，特定的WT敏感的PtdIns 4-激酶对于维持激动剂敏感的多磷肌醇脂库是至关重要的，
The synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P-2], the immediate precursor of intracellular signals generated by calcium mobilizing hormones and growth factors, is initiated by the conversion of phosphatidylinositol to phosphatidylinositol 4-phosphate [PtdIns(4)P] by phosphatidylinositol 4-kinase (PtdIns 4-kinase), Although cells contain several PtdIns 4-kinases, the enzyme responsible for regulating the synthesis of hormone-sensitive PtdIns(4,5)P-2 pools has not been identified, In this report we describe the inhibitory effect of micromolar con centrations of wortmannin (WT) on the synthesis of hormone-sensitive PtdIns(4)P and PtdIns(4,5)P-2 pools in intact adrenal glomerulosa cells, and the presence of a WT- sensitive PtdIns 4-kinase in adrenocortical extracts, In addition to its sensitivity to the PtdIns 3 kinase inhibitor WT, this enzyme is distinguished from the recognized membrane-bound PtdIns 4-kinases by its molecular size and weak membrane association, Inhibition of this PtdIns 4 kinase by WT results in rapid loss of the hormone-sensitive PtdIns(4,5)Pz pool in angiotensin II-stimulated glomerulosa cells, Consequently, WT treatment inhibits the sustained but not the initial increases in inositol 1,4,5 trisphosphate and cytoplasmic [Ca2+] in a variety of agonist-stimulated cells, including adrenal glomerulosa cells, NIH 3T3 fibroblasts, and Jurkat lymphoblasts. These results indicate that a specific WT-sensitive PtdIns 4-kinase is critical for the maintenance of the agonist-sensitive polyphosphoinositide pool in several cell types,