COORDINATE DEPRESSION OF BRADYKININ RECEPTOR RECYCLING AND MICROTUBULE-DEPENDENT TRANSPORT BY TAXOL
COORDINATE DEPRESSION OF BRADYKININ RECEPTOR RECYCLING AND MICROTUBULE-DEPENDENT TRANSPORT BY TAXOL
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DOI：
10.1073/pnas.91.16.7812
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发表时间：
1994-08-02
影响因子：
11.1
通讯作者：
SHEETZ, MP
中科院分区：
文献类型：
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作者：
HAMMALVAREZ, SF;ALAYOF, BE;SHEETZ, MP
显著的心血管副作用限制了紫杉醇作为抗癌药物的使用。由于紫杉醇能抑制胞内囊泡运动，因此细胞膜动力学的降低与紫杉醇之间存在联系。紫杉醇引起的膜再循环减少可抑制激动剂诱发的内皮细胞内Ca 2+信号传导，导致内皮依赖性血管舒张。缓激肽和ATP是引起内皮细胞中Ca 2+瞬变的两种激动剂。由于缓激肽受体-激动剂复合物被内化和回收，而ATP激动剂-受体复合物则没有，我们预期紫杉醇对回收的抑制会降低缓激肽而不是ATP受体活性。我们发现，紫杉醇抑制（i）微管依赖性囊泡转运的频率（至对照组的41%）和速度（至对照组的55%）和（ii）缓激肽诱发的牛主动脉内皮细胞胞浆Ca 2+瞬变（至对照组的76%）。在研究缓激肽受体脱敏，这反映了受体再循环，我们证明，紫杉醇抑制缓激肽诱发的钙瞬变50%。紫杉醇没有显着改变ATP诱发的Ca 2+瞬变无论是单次曝光或脱敏实验。我们认为，紫杉醇的缓激肽诱发的Ca 2+瞬变的减少是由于改变微管依赖的膜再循环。本报告描述了紫杉醇通过影响囊泡运输和膜运输途径改变质膜组成的能力。这一发现提供了一个可能的机制，紫杉醇可以大大改变心血管功能。
Significant cardiovascular side effects have limited the use of taxol as an anticancer drug. A link between decreased plasma membrane dynamics and taxol has been implied because taxol can inhibit intracellular vesicle movements. Reduced membrane recycling caused by taxol could inhibit agonist-evoked Ca2+ signaling within endothelial cells, resulting in endothelium-dependent vasodilation. Bradykinin and ATP are two agonists that evoke Ca2+ transients in endothelial cells. Since the bradykinin receptor-agonist complex is internalized and recycled whereas the ATP agonist-receptor complex is not, we expected that a taxol inhibition of recycling would decrease bradykinin but not ATP receptor activity. We found that taxol depresses (i) the frequency (to 41% of control) and velocity (to 55% of control) of microtubule-dependent vesicle transport and (ii) bradykinin-evoked cytosolic Ca2+ transients (to 76% of control) in bovine aortic endothelial cells. In studying bradykinin receptor desensitization, which reflects receptor recycling, we demonstrate that taxol inhibits bradykinin evoked Ca2+ transients by 50%. Taxol did not significantly alter ATP-evoked Ca2+ transients in either single-exposure or desensitization experiments. We suggest that taxol's reduction of bradykinin-evoked Ca2+ transients is due to altered microtubule dependent membrane recycling. This report describes taxol's ability to alter plasma membrane composition through effects on vesicle transport and membrane trafficking pathways. This finding provides a possible mechanism by which taxol can substantially alter cardiovascular function.