H2O2

Abstract

Increasing evidence implicates hydrogen peroxide (H2O2) as an intracellular and intercellular signaling molecule that can influence processes from embryonic development to cell death. Most research has focused on relatively slow signaling, on the order of minutes to days, via second messenger cascades. However, H2O2 can also mediate subsecond signaling via ion channel activation. This rapid signaling has been examined most thoroughly in the nigrostriatal dopamine (DA) pathway, which plays a key role in facilitating movement mediated by the basal ganglia. In DA neurons of the substantia nigra, endogenously generated H2O2 activates ATP-sensitive K+ (K-ATP) channels that inhibit DA neuron firing. In the striatum, H2O2 generated downstream from glutamatergic AMPA receptor activation in medium spiny neurons acts as a diffusible messenger that inhibits axonal DA release, also via K-ATP channels. The source of dynamically generated H2O2 is mitochondrial respiration; thus, H2O2 provides a novel link between activity and metabolism via K-ATP channels. Additional targets of H2O2 include transient receptor potential (TRP) channels. In contrast to the inhibitory effect of H2O2 acting via K-ATP channels, TRP channel activation is excitatory. This review describes emerging roles of H2O2 as a signaling agent in the nigrostriatal pathway and basal ganglia neurons.