Glutathione modulates Ca(2+) influx and oxidative toxicity through TRPM2 channel in rat dorsal root ganglion neurons

Mustafa Nazıroğlu, Cemil Özgül, Bilal Çiğ, Salih Doğan, Abdulhadi Cihangir Uğuz
Journal of Membrane Biology 2011, 242 (3): 109-18
Glutathione (GSH) is the most abundant thiol antioxidant in mammalian cells and maintains thiol redox in the cells. GSH depletion has been implicated in the neurobiology of sensory neurons. Because the mechanisms that lead to melastatin-like transient receptor potential 2 (TRPM2) channel activation/inhibition in response to glutathione depletion and 2-aminoethyldiphenyl borinate (2-APB) administration are not understood, we tested the effects of 2-APB and GSH on oxidative stress and buthionine sulfoximine (BSO)-induced TRPM2 cation channel currents in dorsal root ganglion (DRG) neurons of rats. DRG neurons were freshly isolated from rats and the neurons were incubated for 24 h with BSO. In whole-cell patch clamp experiments, TRPM2 currents in the rat were consistently induced by H(2)O(2) or BSO. TRPM2 channels current densities and cytosolic free Ca(2+) content of the neurons were higher in BSO and H(2)O(2) groups than in control. However, the current densities and cytosolic Ca(2+) release were also higher in the BSO + H(2)O(2) group than in the H(2)O(2) alone. When intracellular GSH is introduced by pipette TRPM2 channel currents were not activated by BSO, H(2)O(2) or rotenone. BSO and H(2)O(2)-induced Ca(2+) gates were blocked by the 2-APB. Glutathione peroxidase activity, lipid peroxidation and GSH levels in the DRG neurons were also modulated by GSH and 2-APB inhibition. In conclusion, we observed the protective role of 2-APB and GSH on Ca(2+) influx through a TRPM2 channel in intracellular GSH depleted DRG neurons. Since cytosolic glutathione depletion is a common feature of neuropathic pain and diseases of sensory neuron, our findings are relevant to the etiology of neuropathology in DRG neurons.

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