Coordinate depression of bradykinin receptor recycling and microtubule- dependent transport by taxol

S. F. Hamm-Alvarez, B. E. Alayof, H. M. Himmel, P. Y. Kim, A. L. Crews, H. C. Strauss, Michael Sheetz

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)7812-7816
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number16
DOIs
StatePublished - Aug 10 1994
Externally publishedYes

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