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.
Hamm-Alvarez
S F
SF
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
Alayof
B E
BE
Himmel
H M
HM
Kim
P Y
PY
Crews
A L
AL
Strauss
H C
HC
Sheetz
M P
MP
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D008857:Microscopy, Interference; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D018002:Receptors, Bradykinin / Q000378:metabolism*
D018002:Receptors, Bradykinin; D000255:Adenosine Triphosphate; D017239:Paclitaxel; D002118:Calcium