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Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.

Publication ,  Journal Article
Boehmerle, W; Zhang, K; Sivula, M; Heidrich, FM; Lee, Y; Jordt, S-E; Ehrlich, BE
Published in: Proc Natl Acad Sci U S A
June 26, 2007

Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (InsP(3))-mediated Ca(2+) signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP(3) receptor (InsP(3)R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca(2+) signaling. When NCS-1 protein levels recovered, so did InsP(3)-mediated Ca(2+) signaling. Inhibition of the Ca(2+)-activated protease mu-calpain prevented alterations in phosphoinositide-mediated Ca(2+) signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by mu-calpain in vitro and that mu-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates mu-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP(3)mediated Ca(2+) signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 26, 2007

Volume

104

Issue

26

Start / End Page

11103 / 11108

Location

United States

Related Subject Headings

  • Time Factors
  • Signal Transduction
  • Rats
  • Phosphatidylinositols
  • Peripheral Nervous System Diseases
  • Paclitaxel
  • Neuropeptides
  • Neurons
  • Neuronal Calcium-Sensor Proteins
  • Humans
 

Citation

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Boehmerle, W., Zhang, K., Sivula, M., Heidrich, F. M., Lee, Y., Jordt, S.-E., & Ehrlich, B. E. (2007). Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci U S A, 104(26), 11103–11108. https://doi.org/10.1073/pnas.0701546104
Boehmerle, Wolfgang, Kun Zhang, Michael Sivula, Felix M. Heidrich, Yashang Lee, Sven-Eric Jordt, and Barbara E. Ehrlich. “Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.Proc Natl Acad Sci U S A 104, no. 26 (June 26, 2007): 11103–8. https://doi.org/10.1073/pnas.0701546104.
Boehmerle W, Zhang K, Sivula M, Heidrich FM, Lee Y, Jordt S-E, et al. Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11103–8.
Boehmerle, Wolfgang, et al. “Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.Proc Natl Acad Sci U S A, vol. 104, no. 26, June 2007, pp. 11103–08. Pubmed, doi:10.1073/pnas.0701546104.
Boehmerle W, Zhang K, Sivula M, Heidrich FM, Lee Y, Jordt S-E, Ehrlich BE. Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11103–11108.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 26, 2007

Volume

104

Issue

26

Start / End Page

11103 / 11108

Location

United States

Related Subject Headings

  • Time Factors
  • Signal Transduction
  • Rats
  • Phosphatidylinositols
  • Peripheral Nervous System Diseases
  • Paclitaxel
  • Neuropeptides
  • Neurons
  • Neuronal Calcium-Sensor Proteins
  • Humans