H₂O₂Signaling in the Nigrostriatal Dopamine Pathway Via ATP-Sensitive Potassium Channels: Issues and Answers

Abstract

The role of reactive oxygen species (ROS) as signaling agents is increasingly appreciated. Studies of ROS functions in the central nervous system, however, are only in their infancy. Using fast-scan cyclic voltammetry and fluorescence imaging in brain slices, the authors discovered that hydrogen peroxide (H2O2) is an endogenous regulator of dopamine release in the dorsal striatum. Given the key role of dopamine in motor, reward, and cognitive pathways, regulation by H2O2 has implications for normal dopamine function, as well as for dysfunction of dopamine transmission. In this review, data are summarized to show that H2O2 is a diffusible messenger in the striatum, generated downstream from glutamate receptor activation, and an intracellular signal in dopamine neurons of the substantia nigra, generated during normal pacemaker activity. The mechanism by which H2O2 inhibits dopamine release and dopamine cell activity is activation of ATP-sensitive K+ (KATP) channels. Characteristics of the neuronal and glial antioxidant networks required to permit H2O2 signaling, yet prevent oxidative damage, are also considered. Lastly, estimates of physiological H2O2 levels are discussed, and strengths and limitations of currently available methods for H2O2 detection, including fluorescence imaging using dichlorofluorescein (DCF) and the next generation of fluorescent probes, are considered.

Adiponectin inhibits palmitate-induced apoptosis through suppression of reactive oxygen species in endothelial cells: involvement of cAMP/protein kinase A and AMP-activated protein kinase

“…In this study, we also showed that palmitate induced apoptosis through ROS generation in HUVECs. Despite recent studies concerning the role of ROS as a signaling molecule (Avshalumov et al 2007), the imbalance between detoxifying antioxidant system and ROS generation leads to divergent pathological disorders (Stocker & Keaney 2004, Schulze & Lee 2005, Takimoto & Kass 2007. Accumulating evidence also indicates that ROS mediates endothelial cell apoptosis to many different stresses such as bacterial toxin, cytokine, and neuronal hormone (Deshpande et al 2000, Suematsu et al 2002, Sylte et al 2004, Kuckleburg et al 2008.…”

ATP-sensitive potassium channels: novel potential roles in Parkinson’s disease

“…Other investigations of the protection mechanism of mitochondrial K + channel suggest that the opening of mito-K ATP induced by increasing reactive oxygen species (ROS) production combines with blunting mitochondrial Ca 2+ accumulation, which finally improves the mitochondrial energy production [20] . As hydrogen peroxide (H 2 O 2 ) generate in all cells by mitochondrial respiration, Avshalumov MV examined regulation of K ATP channels in nigral dopaminergic neurons to certain the relationship between H 2 O 2 with mito-K ATP channels [21][22] . The observation confirms an essential role of H 2 O 2 in activating K ATP channels.…”

“…In addition, other intracellular factors like phosphoinositol phosphates (e.g. PIP2), G proteins, or protein kinases could modulate the metabolic sensitivity of K ATP channels as well [13,22] . One has to be highlighted is that the regulation of cell activity by H 2 O 2 and metabolic sensitivity of mito-K ATP channels is mainly determined by the alternative expression of SUR subunits.…”

“…One has to be highlighted is that the regulation of cell activity by H 2 O 2 and metabolic sensitivity of mito-K ATP channels is mainly determined by the alternative expression of SUR subunits. After acute rotenone-induced K ATP channel activation in mouse brain slices, only highly responsive dopaminergic neurons expressing the K ATP channel subunits SUR1 and Kir6.2 [20][21][22] . The other population of dopaminergic neurons in substantia nigra pars compacta (SNpc), which express the other SUR isoform, maintain their pacemaker activity as a response to their partial mitochondrial respiratory chain complex I (CXI) inhibition [13,15,21,23] .…”

Classification of H2O2as a Neuromodulator that Regulates Striatal Dopamine Release on a Subsecond Time Scale

“…Although DCF fluorescence imaging is not suitable for quantitative evaluation of absolute H 2 O 2 concentration, this dye can be used to monitor relative differences in basal and stimulated levels of H 2 O 2 . 19,44 Despite the fact that MSNs are electrically silent in brain slices, basal DCF fluorescence is detected in all cells tested, presumably reflecting tonic H 2 O 2 production through mitochondrial respiration required to maintain ion gradients. 22 During local electrical stimulation of dorsal striatum in ex vivo brain slices, each pulse of a stimulus train (e.g., 30 pulses, 10 Hz) elicits a single action potential in recorded MSNs ( Figure 2B); these spikes are AMPAR-dependent, as discussed further below.…”