THAPSIGARGIN, A HIGH-AFFINITY AND GLOBAL INHIBITOR OF INTRACELLULAR CA2+ TRANSPORT ATPASES
THAPSIGARGIN, A HIGH-AFFINITY AND GLOBAL INHIBITOR OF INTRACELLULAR CA2+ TRANSPORT ATPASES
复制标题
DOI：
10.1016/0003-9861(92)90416-t
复制
发表时间：
1992-11-01
影响因子：
3.9
通讯作者：
SAGARA, Y
中科院分区：
文献类型：
--
作者：
INESI, G;SAGARA, Y
自古以来，植物Thapsia garganica就因其根提取物产生的皮肤刺激而闻名（1），该根提取物用于肌肉和关节炎症的局部治疗。皮肤刺激作用归因于Rasmussen等人从根提取物中分离的两种化合物，毒胡萝卜素和毒胡萝卜素。(1)并显示在大鼠肥大细胞中释放组胺。毒胡萝卜素是两种化合物中含量最丰富的，是一种倍半萜内酯（图1），其结构已通过光谱学和晶体学方法进行了详细研究（2-5）。据报道，毒胡萝卜素在各种细胞类型中诱导化学介质的释放（6-9）并促进小鼠皮肤中的肿瘤（10）。当发现毒胡萝卜素作用模式的一个特定和有趣的方面时，该试剂产生细胞内Ca '+的升高（11，12）并消耗肌醇-1，4，5-三磷酸盐敏感的Ca 2'储存，而不产生肌醇磷酸盐（13）。这种作用与抑制内质网Ca 2+螯合活性有关（14）。然后确定毒胡萝卜素是所有测试的细胞内Ca 2+转运ATP酶的高亲和力抑制剂（15-18）。毒胡萝卜素作为一种实验工具的重要性在于它能够识别和选择性地干扰细胞内Ca 2+池。然后可以在大量Ca '+依赖性细胞内功能上测试这种干扰的效果（19-25）。此外，由于其高亲和力和特异性，毒胡萝卜素是一个非常有趣的工具，用于ATP酶机制的分子表征，这是负责耦合催化活性与Ca 2+转运。
The plant Thapsia garganica has been known since ancient times (1) for the skin irritation produced by its root extracts which were used for topical treatment of muscle and joint inflammations. The skin irritating effect was attributed to two compounds, thapsigargin and thapsigargicin, isolated from root extracts by Rasmussen et al.(1) and shown to release histamine in rat mast cells. Thapsigargin, the most abundant of the two compounds, is a sesquiterpene lactone (Fig. 1) whose structure was studied in detail by spectroscopic and crystallographic methods (2-5). It has been reported that thapsigargin induces release of chemical mediators in various cell types (6-9) and promotes tumors in mouse skin (10). A specific and interesting aspect of the thapsigargin mode of action came to light when it was found that this agent produces elevation of intracellular Ca’+(11, 12) and depletes inositol-1, 4, 5-triphosphate-sensitive Ca2’stores, without generation of inositol phosphates (13). This effect was related to inhibition of the endoplasmic reticulum Ca2+ sequestering activity (14). It was then established that thapsigargin is a high affinity inhibitor of all tested intracellular Ca2+ transport ATPases (15-18). The importance of thapsigargin as an experimental tool lies in its ability to identify and interfere selectively with intracellular Ca2+ pools. The effect of this interference can then be tested on a large number of Ca’+-dependent intracellular functions (19-25). Furthermore, owing to its high affinity and specificity, thapsigargin is a very interesting tool for the molecular characterization of the ATPase mechanism which is responsible for coupling catalytic activity with Ca2+ transport.