%0 Journal Article
%T Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons
%A Jillian C Belrose
%A Yu-Feng Xie
%A Lynn J Gierszewski
%A John F MacDonald
%A Michael F Jackson
%J Molecular Brain
%D 2012
%I BioMed Central
%R 10.1186/1756-6606-5-11
%X 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.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.Aging is a major risk factor for developing several neurodegenerative diseases. Although the precise reasons are poorly understood, a growing body of evidence suggests that age-related cognitive decline is associated with stereotypic changes in cellular homeostasis which ultimately lead to impaired neuronal function [1]. A leading hypothesis suggests that increased oxidative stress associated with aging predisposes neurons to dysregulated intracellular Ca2+ homeostasis in response to disease causing factors [2]. Accordingly, understanding the relation between oxidative stress and altered Ca2+ homeostasis may provide valuable insight into mechanisms underlying neurodegenerative disease.Glutathione (GSH), the most abundant intracellular reducing agent [3], plays an important role in limiting cellular damage by reactive oxygen and nitrogen species generated as a by-product of aerobic metabolism. Cellular levels of GSH are known to decrease with age [4-9] and the resulting decline in antioxidant defence is viewed as a risk factor contributing to the increased susceptibility to neurodegenerative disease associated with aging.
%K TRPM2
%K Aging
%K Glutathione
%K Oxidative stress
%K Pyramidal neuron
%K Primary hippocampal culture
%U http://www.molecularbrain.com/content/5/1/11