Paclitaxel activates SOCE/I_CRAC in dorsal root ganglion neurons: implications for paclitaxel-induced peripheral neuropathy

Paclitaxel (PTX) is one of the most widely used antineoplastic drugs for the treatment of solid cancers. Its mechanism of action involves binding to β-tubulin subunits, leading to the stabilization of microtubule polymers and subsequent cell cycle arrest. Despite its efficacy, PTX is associated with significant adverse effects, most notably peripheral neurotoxicity and neuropathic pain, which represent the primary dose-limiting side effects. In sensory neurons, PTX affects multiple molecular pathways, with early alterations in excitability and calcium signaling following acute drug exposure. To investigate these mechanisms, we employed a combination of calcium imaging, electrophysiological techniques, and pharmacological approaches to explore the role of ORAI channels in the excitability and calcium dynamics of mouse dorsal root ganglion neurons. Our findings reveal that acute exposure to low doses of PTX triggers IP₃-dependent calcium release and activates a store-operated calcium entry through STIM-ORAI dependent I_CRAC. Moreover, acute PTX application induced the activation of a sustained calcium inward current, V_m depolarization and triggered action potential firing that was strongly attenuated by I_CRAC inhibition. Molecular analyses further revealed a significant upregulation of Orai1, Orai2, and Stim2 mRNA levels, accompanied by elevated ORAI1 protein expression, in a rat model of paclitaxel-induced peripheral neuropathy. These results suggest that ORAI and STIM proteins represent promising molecular targets for developing therapies aimed at mitigating the side effects of PTX.