Experimental testing of the role of cytoskeleton in the solution by neurons of problems facing the brain.

Investigation of the influence of cAMP on neuronal electric activity suggests that nerve cells can solve problems using an intraneuronal calculating medium based on the cytoskeleton. When a new problem is posed, this structure has to be disassembled and assembled by the neuronal molecular computer according to the program recorded in DNA. If DNA lacks an appropriate program, the cytoskeleton will not be assembled. In our experiments, fishes which were rotated simultaneously around two mutually perpendicular axes lost their swimming ability, and some dramatic changes were observed in the cytoskeleton of their Mauthner neurons. These changes disappeared after a long-term rest: the cytoskeleton was restored simultaneously with the ability for normal swimming.

[Problems uniting biology, physics, and mathematics. Ideas in the new science]. / Problemy, ob''ediniaiushchie biologiiu, fiziku i matematiku. Idei novoi nauki.

The necessity of launching a new field of science that combines biology, physics, and mathematics for an adequate description of natural-science systems (khaimatika) is substantiated.

[Change in neuronal membrane permeability exposed to adenosine-3',5'-cyclophosphate]. / Izmeneie pronitsaemosti membrany neirona pod deistviem adenozin-3',5'-tsiklofosfata.

Ionic current induced by intracellular injection of cAMP was divided into constituent parts, and the dependence of these components on membrane potential and ionic composition of extracellular medium was demonstrated. The computation shows that practically all background neurone permeability for potassium ions is cAMP-dependent.

Cell molecular computers and biological information as the foundation of nature's laws.

It is proposed to unite the principles of new science mathematics, physics and biology for the description of living creatures. Such description is based on four principles: minimal price of action, optimum prediction, minimal irreversibility, and causality. In this new knowledge of nature not only the molecular biological experimental aspects have to be considered, but also the profound 'meaning' of molecular texts of DNA.

Molecular quantum computer of neuron.

Living cells are controlled by quantum regulators in which the price of action of elementary operations approaches Planck's constant. The description of such systems is based on four principles: (1) minimal price of action principle for control; (2) principle of optimality; (3) minimum irreversibility principle; and (4) the principle of causality.

Mechanical influence and cAMP injection evoke the same reaction of neuron ionic channels.

Intracellular cAMP injection and negative pressure in the patch-electrode increase the interburst closed time of the same potassium ionic channels in the snail neuron membrane. Sodium channels which were registered as change of background noise are activated both by cAMP injection and by negative pressure. These results are considered in connection with data about the unusual biochemistry of the neuron reaction to cAMP.

[The effect of various protein kinase inhibitors on the response of snail neurons to the intracellular injection of cAMP]. / Vliianie razlichnykh ingibitorov proteinkinazy na éffekt vnutrikletochnoi in''ektsii tsAMF v neirony vinogradnoi ulitki.

Drugs preventing cAMP interaction with regulatory subunit of cAMP-dependent protein kinase, tolbutamide and db-cAMP injected into neurons of Helix lucorum decreased the cell response to cAMP, but H-8-a potent inhibitor of this enzyme catalytic subunit did not produce such effect. It is suggested that the neuron electric response to cAMP injection is not caused by protein phosphorylation.

[Input and output channels of quantum biocomputers]. / Vkodnye i vykhodnye kanaly kvantovogo biokomp'iutera.

It is proposed that "Quantum Molecular" computer of a neuron consists of the cell cytoskeleton serving as calculating media and input ionic channel sending a hypersound signal to observe these media. The sound spreads through the media travelling along microtubules and microfilaments and switching between those via molecular bridges which serve as elementary switches. The whole system works like a wave guiding net connecting input ionic channels (which generate different sound signals) and output ionic channels (which are controlled by the processed sound signals). Thus the output of such systems depends on the input (controlled by synaptic activity) and on the construction and state of these calculating media. We think that the sound waves spreading through different calculating media solve different physical problems. The construction of the calculating part of the cytoskeleton, according to the hypothesis, is different in different neurons. It is defined by special protein which is produced by DNA, RNA and protein molecular word processor (during brain development and, may be, education). We comment on how the existence of an extremal computer produces an impact on physics and mathematics exemplified by the optimality principle as substitution of physical relativity principle for a complex problem.

Quantum molecular computer model of the neuron and a pathway to the union of the sciences.

Cyclic nucleotide injection in neurons shows that cAMP controls a new type of membrane permeability. The neuron response to cAMP has a short delay, unusual bioenergetics and is blocked by drugs binding with the regulatory subunit of protein kinase. These data are interpreted in terms of the hypothesis that the controlling system of the living cell is a molecular (DNA, RNA, protein operators with complementary addresses), holographic (quick changeable lattice--cytoskeleton), quantum (each phonon examines whole lattice), hypersound (with wave length 100-10,000 A that does not destroy molecules) system with an inner point of view (molecular coding of questions and answers about quantum processing). Neither an electron, nor a macroscopic computer has an inner point of view.

[A study of the change in conductivity of the neuronal membrane caused by a generator potential using a method of computer modeling]. / Izuchenie izmeneniia provodimosti membrany neirona, vyzyvaiushchego generatornyi potential, metodom modelirovaniia na EVM.

Injection of cAMP induces in snail neurons generator potential, which is related to an increase of sodium and decrease of potassium permeability of the neuron outer membrane. A model is proposed which takes into account cAMP diffusion inside the neuron from the injection place and interaction of these molecules with the intercellular system controlling permeability of the outer membrane. Resulting impulse generation induces calcium ions current through the outer membrane. The model also considers calcium diffusion toward cAMP and its effect on the rate of the enzyme work destroying cAMP. Agreement between the calculations of ionic current I(t) and the experiment permits determination of the model parameters and calculation of the observed change of time distribution of nerve impulses when calcium input is significant.

Unusual biochemistry of changes in neuron membrane permeability evoked by cAMP.

Influence of different metabolic poisons on cAMP-evoked neuron membrane permeability is investigated. Drugs preventing cAMP binding with R subunits of protein kinase decrease the cAMP-evoked current, but the inhibitor of the C subunit. H8, has no effect. The cAMP-dependent current is increased by uncouplers and decreased by inhibitors of glycolysis and oxidative phosphorylation. The mechanism of cAMP action on neuron permeability is discussed.

[Effect of oxidative phosphorylation inhibitors and uncoupling agents on cAMP activity]. / Vliianie ingibitorov i razobshchitelei okislitel'nogo fosforilirovaniia na deistvie tsAMF.

Uncouplers of oxidative phosphorylation increased the speed of substrate oxidation and ATP hydrolysis and raised cAMP induced neuron membrane current. Different inhibitors decreased it. Both effects support the hypothesis that a signal of intracellular injected cAMP spreads to the neuron membrane as a mechanical signal. This signal propagated to the membrane along microtubules which according to this hypothesis serve as a sound generator with metabolic heat pumping.

[General principles of receptor and neuron function]. / Obshchie printsipy raboty retseptorov i neironov.

Experimental data supporting hypothesis about mechanical part in both neuron and receptor intracellular mechanism are presented.

[The role of the electromechanical and reaction-diffusion system of intraneuronal information processing in brain function]. / Rol' élektromekhanicheskoi i reaktsionno-diffuzionnoi sistemy vnutrineironnoi pererabotki informatsii v rabote mozga.

The experimental data of previous papers are considered as a basis for the hypothesis about intraneuronal system controlled by cyclic nucleotides and changing the membrane permeability upon creating the generatory potential. This system is suggested to be an extremal molecular regulator in which the price of action per single operation approximates the physical limit. The electro-mechanical intraneuronal system is capable of solving multidimensional physical problems by means of molecular "digital" hypersound holo-gram coded by DNA molecular text which is an image of functions of target search.

[The role of electro-mechanical and reaction-diffusion systems in the intra-neuron processing of information: effect of in-flow of calcium and intracellular calcium on cAMP activity]. / Rol' élektromekhanicheskoi i reaktsionno-diffuzionnoi sistemy vo vnutrineironnoi pererabotke informatsii: vliianie vkhodiashchego potoka kal'tsiia i vnutrikletochnogo kal'tsiia na éffekt tsAMF.

Influx of calcium ions cannot control a generatory potential induced by the intraneuronal system because calcium ions enter the cell during impulses. These impulses are the result of problem solving and must not influence directly the generatory potential. Therefore cAMP and not calcium controls the permeability of sodium and potassium channels from the inside of the neuron. However the calcium ions and membrane potential of mitochondria affect the impact of cAMP injections. An increase in the intracellular concentration of free Ca2+ induced by the injection of Ca-EGTA buffer with 5.10(-7) M free Ca2+, electric excitation, uncouplers of oxidative phosphorylation or arsenate leads to an increase of cAMP-dependent depolarization and the inward current. The injection of Ca-EGTA buffer with 10(-5) M free Ca2+ and drop in [Ca2+]in by EGTA as well as generation of impulses after cAMP injection decrease the cAMP effect. As rise in [Ca2+]in activates phosphodiesterase and uncouples oxidative phosphorylation, and vanadate in contrast to arsenate suppresses the cAMP effect, a hypothesis is advanced that activating effect of calcium on cAMP action is associated with neuron deenergization.

Hexaammineruthenium as an electron donor to mitochondrial cytochrome oxidase: membrane potential generation in the absence of cytochrome c.

Cytochrome c oxidase can generate membrane potential in the absence of cytochrome c (e.g., in cytochrome c-deficient mitochondria or in proteoliposomes) with hexaammineruthenium as an artificial electron donor. Of several other redox mediators tested, phenazine methosulfate was found to be an efficient artificial substrate for membrane energization by cytochrome oxidase, whereas TMPD, DAD, DCPIP or ferrocyanide are virtually ineffective. The ability of Ru(NH3)6(2+) and phenazine methosulfate to support the generation of delta psi by cytochrome c-oxidase correlates with their effectiveness as electron donors to cytochrome a in the cyanide-inhibited membrane-bound enzyme.

[Intraneuronal information processing. An increase in sodium and decrease in potassium permeability after injection of cyclic nucleotide and mechanical stimulation of the neuron]. / Vnutrineironnaia pererabotka informatsii. Uvelichenie natrievoi i umen'shenie kalievoi pronitsaemosti pri in''ektsii tsiklicheskogo nukleotida i mekhanicheskom razdrazhenii neirona.

In voltage clamp experiments the ionic permeability mechanism of the neuron soma evoked by the injection of cyclic nucleotides can be estimated only by studying the reversal potential. The value of this potential allows to conclude that permeability is mainly increased by opening potential independent sodium channels. A delay of ionic current evoked by cyclic nucleotides is tenfold less than the time of cAMP diffusion to the membrane. This leads to a hypothesis about the cyclic nucleotide dependent mechanical opening of sodium channels.

Neuron generator potentials evoked by intracellular injection of cyclic nucleotides and mechanical distension.

Depolarization of neuron membrane was shown to occur during cAMP injection by means of both iontophoresis and pressure. Distension of the neuron by means of blowing with large volumes of solution without cAMP can produce reversible responses. The time course can be made similar to that of the cAMP effect and the responses can be repeated many times in the same neuron. The effect of cAMP can be differentiated from the mechanical response by injecting small volumes of concentrated solutions. The delay in this depolarization response to cAMP is only 0.1-0.3 s. The calculated time of diffusion from the electrode tip to the membrane is about 10 times greater. The similarity of cAMP and mechanical responses and the short delay of the cAMP effect suggests that a cAMP effect may be mediated by mechanical signals in the cytoskeleton.

[Intraneuronal information processing. Delay in the changes in membrane potential after administration of cyclic nucleotides]. / Vnutrineironnaia pererabotka informatsii. Zaderzhka izmeneniia membrannogo potentsiala posle vvedeniia tsiklicheskikh nukleotidov.

Depolarization of the neuron membrane induced by cyclic adenosine monophosphate (cAMP) was shown both by ionophoresis and by injection with pressure. Swelling of the neuron during the injection of various substances with pressure causes membrane depolarization which is similar to that induced by cAMP. When applying pressure the cAMP effect can be distinguished by introducing small volumes of concentrated solutions. Similarity between the effects of cAMP and mechanical stimulation of the neuron suggests that in both cases the effect involves action of the electromechanical system consisting of microskeleton and micromuscles which regulate permeability of molecular channels. The delay of the effect after the moment of cAMP and cGMP introduction is small, which enables a conclusion concerning their direct interaction with the cytoskeleton.