[Ionotropic receptors of acetylcholine and ATP: the mechanisms of inhibition].

In this review two kinds of receptors connected with ionic channels are analyzed. First kind is the receptor whose channel can be open with acetylcholine; they a named ionotropic cholinoreceptors (AChRn). The second kind is the receptor whose channel can be open with extracellular ATP. They a named ionotropic purinoreceptors and are designated P2X. Mathematical modelling of the kinetics of interactions with agonists and inhibitors of cholinergic and purine receptors has shown that each of the investigated mechanisms of inhibition of postsynaptic currents (competitive block, channel block, allosteric modulation and acceleration of desensitization) has different influence on the basic characteristics of postsynaptic currents. For unambiguous classification of inhibitory substances according to the molecular mechanisms of their action it is necessary to consider: a trend and size of change under inhibitory action of a decay time constant of the agonist-induced currents; dependence of development of changes and of speed of washing out of substance's effect from duration of its action, from number of activations of receptors and its frequency.

Hydrodynamic flow in a synaptic cleft during exocytosis.

It is shown that exocytosis in a chemical synapse may be accompanied by "microjet" formation due to the overpressure that exists in the vesicles. This mechanism may take place either at complete fusion of a vesicle with the presynaptic membrane or in the so-called kiss-and-run mode of neurotransmitter release. A simple hydrodynamic model of the viscous incompressible flow arising in the synaptic cleft is suggested. The occurrence of hydrodynamic flow (microjet) leads to more efficient transport of neurotransmitter than in the case of classical diffusive transport.

Mechanisms of the inhibition of endplate acetylcholine receptors by antiseptic chlorhexidine (experiments and models).

Mechanisms of the inhibition of evoked multiquantal endplate currents (EPC) by chlorhexidine (CHX) were studied in electrophysiological experiments and by mathematical modeling to discriminate between possible channel, receptor, and non-receptor effects of this common antiseptic drug. Experiments were carried out on the isolated neuromuscular preparation of the cut m. sartorius of the frog Rana ridibunda. The nerve-stimulation-evoked endplate currents were measured by standard double microelectrode technique. For the mathematical simulation, a method based on the solution of a system of ordinary differential equations was used. CHX in milimolar concentrations suppressed the amplitude and shortened the evoked EPC. Recovery of the EPC amplitude was very slow, and EPC shortening persisted during 30-40 min washout of the drug. There is no indication that CHX competes for acetylcholine or carbachol binding site(s). A comparison of the experimental data with mathematical simulation made it possible to construct a reliable kinetic scheme, which describes the action of CHX. CHX induces a combined slow blockade of the open ionic channel and long-lasting allosteric inhibition of the nicotinic acetylcholine receptor. The very slow washout of the drug in terms of EPC amplitude and virtually no recovery of the shortened EPC time course might substantiate certain caution to avoid unintentional high-dose application during its antibacterial application.

Model of concentration changes across the synaptic cleft during a single quantum release.

A model of concentration changes across the synaptic cleft during a single quantum release is presented that can be used for description and characterization of the kinetic in postsynaptic current development under the influence of different antagonists, modulators, desensitization promoters or complex channel blockers. The model enables the calculation of the relative number of open channels as a function of time for two standard cases - when acetylcholinesterase (AChE) is either active or inhibited. One outcome of the present model is that the variable part of AChE activity is zero at the moment of acetylcholine (Ach) release and then increases. This is in contrast to common view that the activity of AChE at the initial moment of release of quanta is maximal and decreases over the time course of quantum action. However, the model explains why non-quantal ACh leakage from the nerve terminal creating a concentration of approximately 10(-8) mol.l(-1) in the cleft can escape hydrolysis by intrasynaptically located cholinesterase and reach the subsynaptic membrane. The model can also be used for theoretical considerations of time and amplitude changes during repetitive nerve-evoke quanta release.

Mechanisms of the effect of 1,1-dimethyl-3-hydroxybutyl phosphonic acid derivatives on synaptic transmission in neuromuscular junction.

We studied the effect of homologues derivatives of 1,1-dimethyl-3-hydroxybutyl phosphonic acid on synaptic transmission in frog neuromuscular junction. Here we reviewed general mechanisms of inhibition of the postsynaptic current.

[Dependence of the concentration of the demi-maximal action of a channel blocker on the agonist concentration].

Based on the analysis of kinetic scheme of blocking of open channels at any number of blocker binding sites, the dependence of current on blocker concentration was found. A variant of this dependence for a trapping blocker was also found. The restrictions of the applicability of the Hill equation and the necessity of taking into account the dependence of the concentration of demi-maximal blocker action (IC50) on the concentration of agonist were shown.

[Study of giant depolarizing activity in the neonatal hippocampal neurones]. / Issledovanie mekhanizma vozniknoveniya gigantskikh depoliariziruiushchikh potentsialov v neironakh gippokampa novorozhdennykh krys.

Spontaneous oscillatory activity is a general feature of developing neural networks. Early in postnatal development, spontaneous network-driven events, termed giant depolarizing potentials (GDPs), occur synchronously over the entire hippocampus. By performing simulation of hippocampal network with using physiology parameters of the neurons and its network from the present experiments and literature dates, we investigated the participation of the different components of network in the generation of GDPs. Comparing the results of the model and in vitro experiments we conclude that are necessary for the GDP generation involvement the activation of GABAergic, glutamatergic inputs and perhaps gap junction.

[The reconstruction of the dynamics of acetylcholine concentration in synaptic cleft in response to a monoquantum signal]. / Rekonstruktsiia dinamiki izmeneniia kontsentratsii atsetilkholina v sinapticheskoi shcheli pri odnokvantovom signale.

By using the experimental data and the model of cholinereceptor activation kinetics in frog nervous-muscular junction, the function of acetylcholine release from the nervous terminal and the function of acetylcholinesterase activity in synaptic cleft were reproduced and approximated. These functions can be used in modeling the influence of blockers and other biogenic postsynaptic modulators on synaptic transfer.

Serotonin modulates neuromuscular transmission in frogs.

The effect of 5-hydroxytryptamine (serotonin) on neuromuscular transmission in frog skeletal muscle was studied using voltage clamp technique. Serotonin produced no effect on end-plate currents during low frequency electrical stimulation of the motor nerve, but increased the amplitude depression of multiquantal currents during high-frequency stimulation similar to motor commands fired by motoneurons. It was shown that the inhibitory effect of serotonin on neuromuscular transmission is determined by slow potential-dependent block of open ionic channels in the postsynaptic membrane accumulating during rhythmic activation of the synapse.

[Modeling of the two wave response of ATP receptors to jumps of the agonist concentration in pheochromocytoma cells]. / Modelirovanie dvukh voln otveta ATP-retseptorov kletok feokhromotsitomy na skachok kontsentratsii agonista.

A model for the kinetics of conformational transitions of ionotropic ATP receptors in pheochromocytoma cells was elaborated. The contribution of the states of ionotropic receptors (upon the blockage of the "open" channel state) to the kinetics of postsynaptic currents was estimated at mediator concentrations studied. The model enables one to determine the contribution of various conformational states of the receptor, in particular in the "closed" state, to the dynamics of ionic current that is registered upon stimulation of ATP receptors. It is shown that after the cessation of the agonist application, a secondary current wave can arise. The rate constants for conformational transitions of ATP receptors were determined.

Mechanism of organization of different types of directed movements.

This article considers the mechanism for construction of movements in biological systems as a means of reducing excess degrees of freedom of a motor organ. It is suggested that each type of excess of degrees of freedom is reduced by one of the hierarchically coordinated systems of motor control. Detailed consideration is given to mechanisms for reducing the dynamic excess of a motor organ, the kinematic excess associated with polyarticular motor organs, and the kinematic excess of the desired trajectory. A functional scheme is developed for a motor control system which reduces these excess degrees of freedom, and the control processes for various types of movement were studied by computer modeling.

[The mechanism of the organization of the types of goal-directed movements]. / Mekhanizm organizatsii nekotorykh tipov tselenapravlennykh dvizhenii.

A possible organization of motor control during moving from a distant point to a purposive one is considered as a way of reduction of three excessive degrees of freedom at hierarchically coordinated levels of motor control. Computer simulation of such movement organization showed its insensitivity to dynamic noise, fluctuations in driving parameters, deviations, delays, and "clutches" of separate joints.