BACKGROUND: Glutathione (GSH) plays an important role in neuronal oxidant 
defence. Depletion of cellular GSH is observed in neurodegenerative diseases and 
thereby contributes to the associated oxidative stress and Ca2+ dysregulation. 
Whether depletion of cellular GSH, associated with neuronal senescence, directly 
influences Ca2+ permeation pathways is not known. Transient receptor potential 
melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel 
expressed in several cell types including hippocampal pyramidal neurons. 
Moreover, activation of TRPM2 during oxidative stress has been linked to cell 
death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting 
they may directly contribute to Ca2+ dysregulation associated with neuronal 
senescence. Herein, we explore the relation between cellular GSH and TRPM2 
channel activity in long-term cultures of hippocampal neurons.
RESULTS: In whole-cell voltage-clamp recordings, we observe that TRPM2 current 
density increases in cultured pyramidal neurons over time in vitro. The observed 
increase in current density was prevented by treatment with NAC, a precursor to 
GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro 
with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 
currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through 
a thiol-independent mechanism, and produces a 3.5-fold shift in the 
dose-response curve generated by ADPR, the intracellular agonist for TRPM2.
CONCLUSION: These results indicate that GSH plays a physiologically relevant 
role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This 
interaction may play an important role in aging and neurological diseases 
associated with depletion of GSH.