Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior.

Modulation of corticostriatal synaptic activity by dopamine is required for normal sensorimotor behaviors. After loss of nigrostriatal dopamine axons in Parkinson's disease, l-3,4-dihydroxyphenlalanine (l-DOPA) and dopamine D2-like receptor agonists are used as replacement therapy, although these drugs also trigger sensitized sensorimotor responses including dyskinesias and impulse control disorders. In mice, we lesioned dopamine projections to the left dorsal striatum and assayed unilateral sensorimotor deficits with the corridor test as well as presynaptic corticostriatal activity with the synaptic vesicle probe, FM1-43. Sham-lesioned mice acquired food equivalently on both sides, while D2 receptor activation filtered the less active corticostriatal terminals, a response that required coincident co-activation of mGlu-R5 metabotropic glutamate and CB1 endocannabinoid receptors. Lesioned mice did not acquire food from their right, but overused that side following treatment with l-DOPA. Synaptic filtering on the lesioned side was abolished by either l-DOPA or a D2 receptor agonist, but when combined with a CB1 receptor antagonist, l-DOPA or D2 agonists normalized both synaptic filtering and behavior. Thus, high-pass filtering of corticostriatal synapses by the coordinated activation of D2, mGlu-R5, and CB1 receptors is required for normal sensorimotor response to environmental cues.

A substrate switch: a new mode of regulation in the methionine metabolic pathway.

We propose a simple mathematical model of liver S -adenosylmethionine (AdoMet) metabolism. Analysis of the model has shown that AdoMet metabolism can operate under two different modes. The first, with low metabolic rate and low AdoMet concentration, serves predominantly to supply the cell with AdoMet, the substrate for various cellular methylation reactions. The second, with high metabolic rate and high AdoMet concentration, provides an avenue for cleavage of excess methionine and can serve as a source of cysteine when its increased synthesis is necessary. The switch that triggers interconversion between the "low" and "high" modes is methionine concentration. Under a certain set of parameters both modes may coexist. This behavior results from the kinetic properties of (i) the two isoenzymes of AdoMet synthetase, MATI and MATIII, that catalyse AdoMet production; one is inhibited by AdoMet, whereas the other is activated by it, and (ii) glycine- N -methyltransferase that displays highly cooperative kinetics that is different from that of other AdoMet-dependent methyltransferases. Thus, the model provides an explanation for how different cellular needs are met by regulation of this pathway. The model also correctly identifies a critical role for glycine N -methyltransferase in depleting excess methionine in the high mode, thus avoiding the toxicity associated with elevated levels of this essential amino acid.

Adenine nucleotide synthesis in human erythrocytes depends on the mode of supplementation of cell suspension with adenosine.

In suspensions of washed human erythrocytes, adenosine added in a single dose to concentrations of 0.1-10.0 mmol/l suspension was deaminated at rates ranging from 10 to 50 mmol/l cells h. The sum of adenosine, inosine, and hypoxanthine concentrations in the suspension, as well as the intracellular concentration of ATP, remained constant. In the presence of 25-50 mmol/l orthophosphate, addition of a single dose of adenosine into erythrocyte suspension increased the ATP concentration by up to 280% of the initial level. If the initial adenosine concentrations were greater than 5 mmol/l suspension, ATP increased independently of adenosine concentration to the level determined only by the concentration of orthophosphate. After orthophosphate was returned to its initial level, ATP in erythrocytes began to decrease. In the presence of coformycin, erythrocytes utilised adenosine at a rate of 0.2-0.3 mmol/l cells h. Their adenylate pool increased at a rate of 0.10-0.16 mmol/l cells h for several hours, but intracellular ATP increased only slightly. The energy charge of cells decreased significantly from 0.86 +/- 0.05 (control) to 0.82 +/- 0.06. Adenosine continuously pumped into erythrocyte suspensions at rates of 0.02-5.0 mmol/l cells h for several hours caused the adenylate pool of erythrocytes and intracellular ATP to increase synchronously at a rate of 0.02-0.35 mmol/l cells h. The energy charge of these erythrocytes increased significantly up to 0.91 +/- 0.03. After pumping of adenosine was stopped, the intracellular ATP and the adenylate pool began to decrease, returning sometimes to the initial level in 2-3 h.

Product activation of human erythrocyte AMP deaminase.

IMP was found to activate AMP deaminase in crude glucose-depleted human erythrocyte lysates. Activation of the enzyme by IMP is due to prevention of the inhibitory effect of inorganic phosphate. At 1 mM AMP and 2-3 mM phosphate the addition of 2-5 mM IMP accelerates the AMP deamination two to three times.

[Energy-dependent processes and metabolism of adenylates in human erythrocytes]. / Energozavisimye protsessy i metabolizm adenilatov v éritrotsitakh cheloveka.

Amphotericin B (1-3 mg/l) decreases the ATP content in erythrocytes by 11-26% and stimulates the K+ efflux but has no effect on the adenylate pool. Adenosine added to the erythrocyte suspension increases the adenylate pool, maintains a high intracellular ATP level for 6-8 hours of incubation at 37 degrees C and diminishes the amphotericin B-induced leakage of K+. Incubation of erythrocytes without glucose for 4-5 hours leads to a 20-50% loss of ATP accompanied by a significant reduction of the adenylate pool. Further addition of glucose partly restores the ATP level. In the presence of adenosine the ATP concentration is restored far more pronounced reaching nearly the original level due to the increase of the adenylate pool.