H 2 O 2

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.