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

Content Provider	PubMed Central
Author	Wolfgang, Boehmerle Zhang, Kun Sivula, Michael Heidrich, Felix M. Lee, Yashang Jordt, Sven-eric Ehrlich, Barbara E.
Copyright Year	2007
Abstract	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 Ca2+ 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 3R) 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 Ca2+ signaling. When NCS-1 protein levels recovered, so did InsP 3-mediated Ca2+ signaling. Inhibition of the Ca2+-activated protease μ-calpain prevented alterations in phosphoinositide-mediated Ca2+ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by μ-calpain in vitro and that μ-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates μ-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP 3mediated Ca2+ signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.
Related Links	http://dx.doi.org/10.1073/pnas.0701546104
Ending Page	11108
Page Count	6
Starting Page	11103
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	26
Volume Number	104
Language	English
Publisher	National Academy of Sciences
Publisher Date	2007-06-26
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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

Protection of Neuronal Calcium Sensor 1 Protein in Cells Treated with Paclitaxel

Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism

Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism

DISCRETE PROTEOLYSIS OF NEURONAL CALCIUM SENSOR 1 (NCS-1) BY μ-CALPAIN DISRUPTS CALCIUM BINDING

Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity

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The Structure of Neuronal Calcium Sensor-1 in Solution Revealed by Molecular Dynamics Simulations

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

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