Paclitaxel acutely activates ICRAC in sensory neurons: implications for paclitaxel-induced peripheral neuropathy

Paclitaxel (PTX) is one of the most widely used antineoplastic drugs in several cancers. The PTX action mechanism involves the binding to the β-tubulin subunits that results in the stabilization of the microtubule polymers and leads to the cell cycle arrest. However, PTX causes various notable adverse events of which peripheral neurotoxicity and neuropathic pain are the most dose-limiting side effects. A number of molecular pathways are affected by PTX in sensory neurons, and among these, alterations in excitability and calcium signalling occur early in response to acute drug application. Here we combined calcium imaging and electrophysiological techniques with a pharmacological approach to characterize in mouse dorsal root ganglion (DRG) neurons the involvement of ORAI channels in the excitability and calcium signals. We found that acute exposure to low dose PTX on DRG neurons activated IP3 - dependent calcium release and the store-operated, calcium release-activated calcium current ICRAC. Lastly, molecular analyses revealed transcriptional upregulation of ORAI1 and STIM2 in a paclitaxel-induced peripheral neuropathy rat model. Our data therefore suggest ORAI and STIM as new molecular targets for the development of therapies against the PTX side effects.