Introduction: Oxidative stress is an aggravating factor of all neurological disorders, including neurodegenerative diseases. It is due to an exaggerated accumulation of reactive oxygen species (ROS) concomitant to decreased reduced glutathione (GSH) levels; the main antioxidant of brain cells produced by astrocytes in large amounts. Cell death triggered by oxidative damage results from intracellular calcium overload which is deleterious to cell activity. The mechanisms involved in these calcium increases are not fully understood. Here, we have thus investigated whether GSH could protect neurons against oxidative stress through the modulation of calcium homeostasis. For this, GSH cell content was manipulated by modulating its metabolism.MM and results: To investigate the link between GSH content and calcium homeostasis, we pre-treated rat astroglioma cells (C6) with sulforaphane (SFN) to increase intracellular GSH levels, or buthionine sulfoximine (BSO) to decrease them, during 24 hours for both treatments. We show using calcium imaging and electrophysiological "patch-clamp" recordings that increasing GSH levels reduced the intracellular mobilization from IP3-sensitive intracellular calcium stores triggered by P2Y purinergic receptor stimulation and the associated membrane conductance changes. By contrast, depleting GSH cellular content by impeding its synthesis with BSO, resulted in a sensitization of Calcium Release Activated Channels (CRAC) evidenced by GSK-7975A, a CRAC blocker. Indeed, in BSOtreated cells, firstly, Ca2+ increases via CRAC were observed under oxidative stress and, secondly, storeoperated calcium entry (SOCE) was revealed after P2Y receptor activation. According to this, quantitative PCR and Western Blotting revealed modified expression of the proteins involved in SOCE, i.e. Orai and STIM, when cells were treated with either SFN or BSO. Conclusion: We conclude that GSH cell content changes impact intracellular Ca 2+ homeostasis in C6 glioma cells likely via sensitization/desensitization mechanisms of Calcium Release Activated Channels (CRAC). GSH depletion due to oxidative stress regulation could thus contribute to the alterations of Ca 2+ homeostasis in astrocytes under pathological conditions.