Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.
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.
Boehmerle
Wolfgang
W
Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
Zhang
Kun
K
Sivula
Michael
M
Heidrich
Felix M
FM
Lee
Yashang
Y
Jordt
Sven-Eric
SE
Ehrlich
Barbara E
BE
D000818:Animals; D020013:Calcium Signaling; D002154:Calpain / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051580:Neuronal Calcium-Sensor Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000209:etiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D010716:Phosphatidylinositols; C101464:frequenin calcium sensor proteins; D002154:Calpain; C449002:mu-calpain; D017239:Paclitaxel