Vajanaphanich M, Schultz C, Rudolf M T, Wasserman M, Enyedi P, Craxton A, Shears S B, Tsien R Y, Barrett K E, Traynor-Kaplan A
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla 92093.
Nature. 1994 Oct 20;371(6499):711-4. doi: 10.1038/371711a0.
Osmoregulation, inhibitory neurotransmission and pH balance depend on chloride ion (Cl-) flux. In intestinal epithelial cells, apical Cl- channels control salt and fluid secretion and are, in turn, regulated by agonists acting through cyclic nucleotides and internal calcium ion concentration ([Ca2+]i). Recently, we found that muscarinic pretreatment prevents [Ca2+]i increases from eliciting Cl- secretion in T84 colonic epithelial cells. By studying concomitant inositol phosphate metabolism, we have now identified D-myo-inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4), as the inositol phosphate most likely to mediate this uncoupling. A novel, membrane-permeant ester prepared by total synthesis delivers Ins(3,4,5,6)P4 intracellularly and confirms that this emerging messenger does inhibit Cl- flux resulting from thapsigargin- or histamine-induced [Ca2+]i elevations.
渗透调节、抑制性神经传递和pH平衡都依赖于氯离子（Cl-）通量。在肠道上皮细胞中，顶端Cl-通道控制盐和液体分泌，反过来又受通过环核苷酸和细胞内钙离子浓度（[Ca2+]i）起作用的激动剂调节。最近，我们发现毒蕈碱预处理可防止[Ca2+]i升高引发T84结肠上皮细胞中的Cl-分泌。通过研究伴随的肌醇磷酸代谢，我们现已确定D-肌醇3,4,5,6-四磷酸（Ins(3,4,5,6)P4）是最有可能介导这种解偶联作用的肌醇磷酸。通过全合成制备的一种新型膜渗透性酯可将Ins(3,4,5,6)P4递送至细胞内，并证实这种新出现的信使确实会抑制毒胡萝卜素或组胺诱导的[Ca2+]i升高所导致的Cl-通量。
