Computer Simulator of Glycine Receptor Activity: A New Window into a Virtual World.

Our study reports computer software that simulates the work of a single glycine receptor (GlyR). GlyRs have been found in various types of tissues, but their most important role seems to be in neurons, where they hyperpolarise membranes by opening chloride transmembrane channels. The software is based on a combination of two blocks. One block describes the Brownian dynamics of charged particle motion in a dielectric medium, and the other block determines the probability and timing of receptor activation. Using this software, the voltage-current dependencies and time curves of the transmembrane current were obtained. The mean value of the simulated anion current (4.5 ± 0.3 pA) is in good agreement with measured values under identical conditions ([Formula: see text] pA). It was shown that there is a condition under which the GlyR anion channel remains active despite a negligible chloride gradient. Virtual experiments allow evaluation of the value of half maximal effective concentration (EC[Formula: see text]) of the GlyR ([Formula: see text] [Formula: see text]M) and confirm that this receptor activates according to a mechanism involving three ligand binding sites. The advantage of the model is the ability to adjust parameters to the precise demands of experimental researchers. Moreover, the introduced algorithm has low computational power demands; therefore, it can be used as a research tool for assistance with structural experiments and applied aspects of neurophysiology.

Glutamate induces H2O2 synthesis in nonsynaptic brain mitochondria.

Mitochondrial reactive oxygen species regulate many important biological processes. We studied H2O2 formation by nonsynaptic brain mitochondria in response to the addition of low concentrations of glutamate, an excitatory neurotransmitter. We demonstrated that glutamate at concentrations from 10 to 50 µM stimulated the H2O2 generation in mitochondria up to 4-fold, in a dose-dependent manner. The effect of glutamate was observed only in the presence of Ca(2+) (20 µM) in the incubation medium, and the rate of calcium uptake by the brain mitochondria was increased by up to 50% by glutamate. Glutamate-dependent effects were sensitive to the NMDA receptor inhibitors MK-801 (10 µM) and D-AP5 (20 µM) and the inhibitory neurotransmitter glycine (5mM). We have shown that the H2O2 formation caused by glutamate is associated with complex II and is dependent on the mitochondrial potential. We have found that nonsynaptic brain mitochondria are a target of direct glutamate signaling, which can specifically activate H2O2 formation through mitochondrial respiratory chain complex II. The H2O2 formation induced by glutamate can be blocked by glycine, an inhibitory neurotransmitter that prevents the deleterious effects of glutamate in brain mitochondria.

Effects of phenobarbital on activity of mitochondrial enzymes in peripheral blood lymphocytes and oxidative phosphorylation in liver mitochondria.

Treatment with phenobarbital (30 mg/kg) for 2 weeks increased succinate dehydrogenase activity in peripheral blood lymphocytes of male rats. In 38% phenobarbital-treated rats succinate-cytochrome c oxidoreductase activity was lower than in the control due to accumulation of cells exhibiting no enzyme activity; in 44% animals this parameter was higher than in the control. The rates of state 3 respiration (oxidation substrate succinate), phosphorylation, and uncoupled respiration in liver mitochondria (oxidation substrate glutamate/malate mixture) increased after 35-day treatment with phenobarbital. The respiratory control and ADP/O ratio for these substrates did not differ from the control.

The uncoupling effect of some psychotropic drugs on oxidative phosphorylation in rat liver mitochondria.

In the present study an attempt to detect influence of some psychotropic drugs on oxidative phosphorylation has been made. Relanium and melipramine were used in the experiments. They are among tranquilizer and antidepressant drug groups respectively. It was shown that both drugs increased the rate of oxygen consumption and displayed uncoupling properties. Mitochondrial respiration raised up slowly after drug addition in the presence of succinate or beta-oxybutyrate as oxidized substrates. If concentration of relanium and melipramine exceeded 1.2 and 0.8 mM respectively the rate of oxygen consumption began to decrease. There was a small reply on addition of ADP in the presence of drugs. At the same time relanium and melipramine decreased respiration rate if they were added at the state 3. It was shown that the drugs increased conductivity of bimolecular phospholipid membranes.