Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R.
Paclitaxel (Taxol) is a microtubule-stabilizing compound that is used for cancer chemotherapy. However, Taxol administration is limited by serious side effects including cardiac arrhythmia, which cannot be explained by its microtubule-stabilizing effect. Recently, neuronal calcium sensor 1 (NCS-1), a calcium binding protein that modulates the inositol-1,4,5-trisphosphate receptor (InsP(3)R), was described as a binding partner of Taxol and as a substrate of calpain. We examined calcium signaling processes in cardiomyocytes after treatment with Taxol to investigate the basis of Taxol-induced cardiac arrhythmia. After treating isolated neonatal rat ventricular myocytes with a therapeutic concentration of Taxol for several hours live cell imaging experiments showed that the frequency of spontaneous calcium oscillations significantly increased. This effect was not mimicked by other tubulin-stabilizing agents. However, it was prevented by inhibiting the InsP(3)R. Taxol treated cells had increased expression of NCS-1, an effect also detectable after Taxol administration in vivo. Short hairpin RNA mediated knockdown of NCS-1 decreased InsP(3)R dependent intracellular calcium release, whereas Taxol treatment, that increased NCS-1 levels, increased InsP(3)R dependent calcium release. The effects of Taxol were ryanodine receptor independent. At the single channel level Taxol and NCS-1 mediated an increase in InsP(3)R activity. Calpain activity was not affected by Taxol in cardiomyocytes suggesting a calpain independent signaling pathway. In short, our study shows that Taxol impacts calcium signaling and calcium oscillations in cardiomyocytes through NCS-1 and the InsP(3)R.
Zhang
Kun
K
Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
Heidrich
Felix M
FM
DeGray
Brenda
B
Boehmerle
Wolfgang
W
Ehrlich
Barbara E
BE
D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D053496:Inositol 1,4,5-Trisphosphate Receptors; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D002154:Calpain; D017239:Paclitaxel
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