A biologic function for an ''orphan'' messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels
A biologic function for an ''orphan'' messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels
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DOI：
10.1073/pnas.93.19.10505
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发表时间：
1996-09-17
影响因子：
11.1
通讯作者：
Barrett, KE
中科院分区：
文献类型：
--
作者：
Ismailov, II;Fuller, CM;Barrett, KE
肌醇磷酸是一类来源于膜肌醇磷脂的水溶性细胞内信号分子，它们经历多种复杂的相互转化途径，其水平在细胞质内受到多种激动剂的动态调节，除了肌醇1,4,5-三磷酸外，对该家族大多数成员的生物学功能知之甚少。具体来说，四磷酸肌醇的生物学功能在很大程度上是模糊的。在本文中，我们报道了d -肌醇3,4,5,6-四磷酸（D-Ins(3,4,5,6)P-4）对上皮Ca2+激活的氯离子通道具有直接的双相（激活/抑制）作用。D-Ins(3,4,5,6)P-4的作用不能被其他肌醇四磷酸异构体所模仿，它依赖于当时的钙浓度，并且当通道被钙调蛋白激酶II磷酸化时受到影响。在受刺激的细胞中，D-Ins(3,4,5,6)P-4对磷酸化通道的主要作用是抑制细胞内钙水平。我们的研究结果表明，迄今为止被认为是“孤儿”信使的分子的生物学功能，他们认为D-Ins(3,4,5,6)P-4的分子靶点是质膜Ca2+激活的氯离子通道。D-Ins(3,4,5,6)P-4和Ca2+对该通道的调节可能对糖尿病肾病和囊性纤维化的疾病状态具有治疗意义。
Inositol phosphates are a family of water-soluble intracellular signaling molecules derived from membrane inositol phospholipids, They undergo a variety of complex interconversion pathways, and their levels are dynamically regulated within the cytosol in response to a variety of agonists, Relatively little is known about the biological function of most members of this family, with the exception of inositol 1,4,5-trisphosphate. Specifically, the biological functions of inositol tetrakisphosphates are Largely obscure. In this paper, we report that D-myo-inositol 3,4,5,6-tetrakisphosphate (D-Ins(3,4,5,6)P-4) has a direct biphasic (activation/inhibition) effect on an epithelial Ca2+-activated chloride channel. The effect of D-Ins(3,4,5,6)P-4 is not mimicked by other inositol tetrakisphosphate isomers, is dependent on the prevailing calcium concentration, and is influenced when channels are phosphorylated by calmodulin kinase II. The predominant effect of D-Ins(3,4,5,6)P-4 on phosphorylated channels is inhibitory at levels of intracellular calcium observed in stimulated cells, Our findings indicate the biological function of a molecule hitherto considered as an ''orphan'' messenger, They suggest that the molecular target for D-Ins(3,4,5,6)P-4 is a plasma membrane Ca2+-activated chloride channel. Regulation of this channel by D-Ins(3,4,5,6)P-4 and Ca2+ may have therapeutic implications for the disease states of both diabetic nephropathy and cystic fibrosis.