缓激肽受体再循环和紫杉醇对微管依赖性运输的协调抑制。
Proceedings of the National Academy of Sciences of the United States of America
(
IF
9.1
)
Pub Date : 1994-08-02
, DOI:
10.1073/pnas.91.16.7812
S F Hamm-Alvarez
1
,
B E Alayof
,
H M Himmel
,
P Y Kim
,
A L Crews
,
H C Strauss
,
M P Sheetz
Affiliation
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
重大的心血管副作用限制了紫杉醇作为抗癌药物的使用。由于紫杉醇可以抑制细胞内囊泡运动，因此暗示了质膜动力学下降与紫杉醇之间存在联系。紫杉酚引起的膜循环减少可抑制激动剂诱发的内皮细胞内Ca2 +信号传导，从而导致内皮依赖性血管舒张。缓激肽和ATP是在内皮细胞中引起Ca2 +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再循环，而ATP激动剂-受体复合物没有被内化和再循环，我们预期紫杉醇抑制再循环会降低缓激肽，但不会降低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（至对照的41％）和速度（至对照的55％），以及（ii）缓激肽诱发的胞质Ca2 +瞬变（至对照的76％）。牛主动脉内皮细胞。在研究缓激肽受体脱敏反应（反映受体再循环）时，我们证明紫杉醇可抑制缓激肽诱发的Ca2 +瞬变50％。在单次暴露或脱敏实验中，紫杉醇均不会显着改变ATP诱发的Ca2 +瞬变。我们建议紫杉醇减少缓激肽诱发的Ca2 +瞬变是由于微管依赖性膜循环改变。该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。
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Coordinate depression of bradykinin receptor recycling and microtubule-dependent transport by taxol.
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.
