Reactive species control uptake of the excitatory neurotransmitter glutamate mainly by oxidation of protein sulfhydryl groups in rat cortical astrocytes [ 42 ]. The NO nitric oxide free radical molecule can freely cross cell membranes, acting as a neurotransmitter, neuromodulator, and messenger. Neuronal NO modulates synaptic activity by regulating neurotransmitter release and takes part in processes involved in synaptic plasticity, such as long-term potentiation, depression and synaptogenesis [ 43 - 46 ].
NO, as a diffusible messenger, increases glutamate release in NMDA receptor activation processes [ 47 ].
Nitric Oxide and Related Substances as Neural Messengers
NADPH oxidases nicotinamide adenine dinucleotide phosphate-oxidase and other sources of superoxide are required for the hippocampal long-term potentiation LTP and hippocampus-dependent memory [ 48 - 51 ]. The NMDA subtype of glutamate receptors consists of a complex of various subunits. Hydrogen peroxide H 2 O 2 is emerging as a ubiquitous messenger in various cells and the brain. Oxidative deamination of monoamines by mitochondrial MAO is accompanied by the reduction of molecular oxygen to H 2 O 2.
Recently, Bao et al. In brief, many experiments have provided evidence that reactive species act as essential signals during physiological pathophysiological processes in cells and the brain. To date, usually, mitochondria are considered as simple cellular energy sources in most scientific literatures. However, there is accumulating evidence that mitochondria function as essential centres for cellular signaling pathways in cells.
According to Aon et al. Namely, the coordination between mitochondria within the network appears to be ROS mediated. Mitochondria are poised at the convergence of most anabolic and catabolic pathways through the tricarboxylic acid cycle. Thus, mitochondria can act as metabolic and redox hubs due to their numerous links to other pathways as inputs sources or outputs sinks.
In addition, growing evidence demonstrates that shapes and spatiotemporal arrangements of mitochondria can be very different in different cell types [ 56 ]. Moreover, activity-dependent mitochondrial redistribution takes place in neurons [ 57 ]. Mitochondria are essential determinant of the excitability and viability of neurons.
In contrast to the textbook description of mitochondria as small spherical organelles in cells, mitochondria in muscular, neuronal and connective tissue are principally filamentous [ 56 , 59 , 60 ].
Mitochondria are functionally connected, i. Mitochondria continuously fuse and divide, and their morphology and intracellular distribution change according to the energy demands of cells [ 61 , 62 ]. Because mitochondria are key players in cellular redox homeostasis and signaling and one of the main sources of free radicals, they play a central role in redox-dependent post-translational reversible oxidative modifications of proteins such as tyrosine phosphatases and protein tyrosine kinases.
Mitochondria also participate in the synthesis and secretion of neurotransmitters. Some essential steps in the metabolism of the major excitatory neurotransmitter glutamate and the principal inhibitory neurotransmitter GABA gamma-aminobutyric acid take place in the mitochondrial tricarboxylic acid cycle [ 63 ]. Besides, mitochondrial monoamine oxidase MAO enzyme performs a key metabolic role in the turnover of serotonin, dopamine, norepinephrine, and epinephrine in the brain [ 64 - 66 ].
Oxidative deamination of monoamines by mitochondrial MAOs is accompanied by the reduction of molecular oxygen to H 2 O 2. Namely, reactive species are generated by mitochondrial monoamine oxidases during natural metabolism of serotonin, norepinephrine, epinephrine, and dopamine. Because oxidative deamination of monoamines by mitochondrial MAOs is a regulated process, reactive species generated during oxidative deaminations may also serve as essential signaling molecules in cells.
In contrast, excess unregulated production of dopamine monoamines can induce overproduction of H 2 O 2 and superoxides via monoamine oxidases, as well as leading to an excess of auto-oxidized dopamine that can cause lipid peroxidation and DNA and protein modifications and interact with the mitochondrial electron transport system. Dopamine can inhibit brain mitochondrial respiration that involves generation of reactive oxygen species [ 67 ].
In addition, dopamine-associated inhibition of mitochondrial respiration is dependent on MAO and H 2 O 2 [ 68 ]. Recently, it was demonstrated that the neurotransmitter dopamine and serotonin 5-HT can reversibly regulate mitochondrial motility and distribution in cultured hippocampal neurons [ 69 , 70 ]. Chen et al.
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In contrast, 5-HT performed a stimulatory effect on mitochondrial movement. However, because mitochondria can function as metabolic and redox hubs, the distribution of mitochondria represents a distribution not only of energy sources but also of metabolic and redox processes. It is very possible that other neurotransmitters, such as norepinephrine and acetylcholine, can also affect mitochondrial movement and distribution. Catecholamines and serotonin and their metabolic products can be either neurotoxic or neuroprotective.
However, catecholamines and serotonin bear free radical scavenging and neuroprotective abilities [ 71 - 74 ]. At high doses, catecholamines induce apoptosis but prevent free radical-mediated neurotoxicity as antioxidants without being coupled to the receptors [ 74 ]. The catechol structure is a fundamental component for the antioxidative effect of catecholamines.
The redox state of the cell is largely linked to the iron and copper redox couple and is maintained within strict physiological limits. Catecholamines can inhibit generation of free radicals by chelating various metals; i.
Serotonin and its precursor have great antioxidant properties in the brain [ 73 ]. Serotonin attenuates free radical-induced neuronal death without being coupled to serotonin receptors in cultured mouse cortical neurons [ 77 ].
Norepinephrine reduces caspase activation and ROS production in cholinergic neurons [ 78 ]. Dopamine and its five receptor subtypes play various roles in the central nervous system. Dopamine exerts its actions through two families of cell surface receptors that belong to the class of G protein-coupled receptors. D1-like receptors D1, D5 stimulate adenylyl cyclases, while D2-like receptors D2, D3, D4 inhibit adenylyl cyclases [ 79 ].
Activation of D1 and D5 receptors produces antioxidant responses [ 80 , 81 ]. Besides, dopamine has concentration-dependent effects on ROS production. It acts as an antioxidant at physiological concentrations, but as a prooxidant at higher concentrations. The neuroprotective outcomes of dopamine can be both receptor-mediated and non-receptor-mediated [ 82 ].
However, dopamine is a potent antioxidant, and when it reduces reactive oxygen species, it is converted into neurotoxic dopamine o quinones. Dopamine o quinone can rapidly recover to dopamine by an ambient antioxidant such as glutathione or ascorbate. In the absence of ambient antioxidants, o quinones form neurotoxic o semiquinones, which are free radicals [ 83 ]. Because mitochondria play key roles in the synthesis and secretion of classical neurotransmitters and that catecholamines and serotonin can act as antioxidants and free radical scavengers, mitochondria can also control redox processes via the regulation of neurotransmitter metabolism and secretion.
Biological functions of nitric oxide
The cellular thiol redox state is a fundamental mediator of numerous signaling, metabolic, and transcriptional processes in cells. The GSH and TRX systems maintain a reduced intracellular redox condition in cells by the reduction of protein thiol groups. Namely, they keep signaling components in a reduced state and are counterbalanced in signaling by oxidative mechanisms.
GSH g-glutamyl-cysteine-glycine, a tripeptide that exists in reduced monomeric GSH and oxidized dimeric forms GSSG is the major thiol antioxidant and redox buffer in cells and is abundant in the cytosol, nuclei, and mitochondria. There is increasing evidence that the glutathione metabolism is abnormal in schizophrenia and that a weakened capacity to synthesize GSH under oxidative stress is a susceptibility factor for schizophrenia. Namely, patients with schizophrenia indicate a deficit in glutathione levels in the prefrontal cortex and cerebrospinal fluid, as well as the reduction of gene expression of GSH-synthesizing enzymes [ 18 , 19 , 85 ].
Pharmacology of GABA and Glycine Neurotransmission
However, glutathione can act as a neuromodulator at the glutamate receptors and as a neurotransmitter at its own receptors. Cabungcal et al. These dysfunctions of GABAergic interneuron can have wide-ranging effects on the neuronal circuitry of prefrontal cortex and its output to additional brain areas.
Glutamate activates two types of glutamate receptors: ionotropic iGluRs and metabotropic glutamate receptors mGluRs [ 88 ]. It is accepted that the glutamate ionotropic NMDA receptor is the principal molecular structure for controlling synaptic plasticity and memory function. NMDAR activation starts several events, including calcium influx, activation of nitric oxide synthase, and superoxide formation [ 89 , 90 ].
Earlier studies have suggested that mitochondria are a principal source of NMDA-induced superoxide production. It is probable that initial superoxide signals produced by NADPH oxidase can stimulate secondary mitochondrial superoxide production. Redox modulation has been recognized as an essential system in the regulation of the NMDA receptor [ 86 ]. Oxidizing agents decrease, but reducing agents enhance NMDA-evoked currents.
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