Given its low reactivity, H 2O 2 does not readily mediate oxidative damage, unless exposed to free metal ions that can catalyze conversion of H 2O 2 to highly reactive These properties limit reactivity ( Cohen 1994) and increase membrane permeability (Ramasarma 1982 Makino and others 2004 Bienart and others 2006, 2007 Adimora and others 2010), so that it is well-suited as both an intracellular signaling agent and as a diffusible messenger. In contrast to many ROS, H 2O 2 is neither a free radical nor an ion. In brain cells, H 2O 2 has been implicated as an intracellular regulator of neuronal activity, growth, and organelle function ( Avshalumov and others 2005 Miller and others 2007b Gerich and Funke 2009 Lee and Rice 2008), as well as a diffusible messenger for neuron-glia signaling ( Atkins and Sweatt 1999) and inter-neuronal communication, including regulation of synaptic transmission and plasticity ( Samanta and others 1998 Auerbach and Segal 1997 Klann and Thiels 1999 Nishida and others 2000 Nemoto and others 2000 Kamsler and Segal 2003 Avshalumov and others 2003 2008). In particular, H 2O 2 is implicated in physiological processes ranging from embryonic development to cell death ( Sundaresan and others 1995 Nishida and others 2000 Rhee 2006 Rhee and others 2005 Stone and Yang 2006 Miller and others 2007b D'Autreaux and Toledano 2007 Coffman and others 2009 Gerich and Funke 2009 Groeger and others 2009 Rigoulet and others 2010). Over the past decade, however, accumulating evidence indicates that ROS are normal components of signaling pathways. OH), are often viewed as toxic waste from cellular oxidative metabolism.O 2 -), hydrogen peroxide (H 2O 2), and the hydroxyl radical (.Reactive oxygen species (ROS), including superoxide ( This review describes emerging roles of H 2O 2 as a signaling agent in the nigrostriatal pathway and other basal ganglia neurons. In contrast to the inhibitory effect of H 2O 2 acting via K ATP channels, TRP channel activation is excitatory. Additional targets of H 2O 2 include transient receptor potential (TRP) channels. The source of dynamically generated H 2O 2 is mitochondrial respiration thus, H 2O 2 provides a novel link between activity and metabolism via K ATP channels. In the striatum, H 2O 2 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. ![]() In DA neurons of the substantia nigra, endogenously generated H 2O 2 activates ATP-sensitive K + (K ATP) channels that inhibit DA neuron firing. 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. However, H 2O 2 can also mediate subsecond signaling via ion channel activation. Most research has focused on relatively slow signaling, on the order of minutes to days, via second messenger cascades. Increasing evidence implicates hydrogen peroxide (H 2O 2) as an intra- and intercellular signaling molecule that can influence processes from embryonic development to cell death.
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