Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R
| Autor: | Barbara E. Ehrlich, Kun Zhang, Felix M. Heidrich, Brenda DeGray, Wolfgang Boehmerle |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Aging
Paclitaxel endocrine system diseases Neuronal Calcium-Sensor Proteins chemistry.chemical_element macromolecular substances Pharmacology Calcium Article Calcium in biology Mice Calcium-binding protein Animals Inositol 1 4 5-Trisphosphate Receptors Myocyte Myocytes Cardiac Calcium Signaling Molecular Biology Calcium signaling biology Calpain Ryanodine receptor Myocardium organic chemicals Neuropeptides Enzyme Activation Mice Inbred C57BL Animals Newborn Neuronal calcium sensor-1 chemistry biology.protein Cardiology and Cardiovascular Medicine Protein Processing Post-Translational Protein Binding |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 49:829-835 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2010.08.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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