Ribonucleotide reductase--a "target" of the action of nitrosomethylurea]

The antitumor and toxic effects of methylnitrosourea (MNU) are determined through its metabolic pathways. In organism MNU is subject to hydrolytic decomposition and denitrosation. It has been shown in vivo studies that MNU abdominal injections of therapeutic doses caused the inhibition of ribonucleotide reductase in mouse spleen, and therefore the DNA synthesis depress. The effect may apparently contribute to antitumor property of MNU. It has been estimated that destruction of M2 subunit of the enzyme is occurred. The relation between the loss of ribonucleotide reductase activity and the inhibition of protein synthesis was discussed. Besides, the cancerogenic and mutagenic properties of MNU were discussed as a result of imbalance of DNA precursor pools. Changes in contents of Fe(3+)-transferrin, ceruloplasmin, methemoglobin in blood and spleen of animals after MNU injections have been found. The changes were reversible after single MNU injection and became irreversible after multiple injections.     

Electrotropic acetylcholine action on the mammalian auricle by means of the "phase plane" trajectories of the action potential

A single sucrose gap techniques has been used to study action potentials and phase plane trajectories of them in atrial trabeculae of the rabbit. Using polynomial representations of current-voltage relationships a model of membrane action potential of atrial myocardial fibres is described and allows an interpretation of recording data from the phase plane trajectories. Our findings show: 1. Increasing extracellular calcium concentration increases a potassium conductivity of the atrial membrane. 2. An anomalous rectification concerning repolarizing currents in atrial fibres decreases with increasing extracellular calcium. 3. Acetylcholine (3.10(-4) g.cm-3) abolishes the anomalous rectification. These results are discussed in relation to previous electrophysiological studies of negative electrotropic effects of acetylcholine in cardiac muscle.     

The "cellular state": the way to regain specificity and diversity in hormone action

In contrast with the high specificity achieved in the effects of hormones and growth factors by their interaction with a large number of membrane receptors, a loss of information seems to take place due to the small number of second messenger systems. To retain specificity one has to consider the cellular state as defined in a state machine by a pattern of activity. Different molecular mechanisms are considered as possible candidates to establish such states following the initial ligand-receptor interaction and the activation of one or several second messengers.     

A quantitative assessment of the "tendon" action of two-joint muscles]

Two-joint muscles are able to transmit mechanical energy between the links of the body having no common joint ("tendon action" of the muscles). It is proposed to calculate difference between control moment power in a joint and the sum of powers developed by all muscles serving this joint in order to determine the direction and rate of mechanical energy transfer through the two-joint muscles. It was shown that in the shock-absorbing phase of support in running two-joint muscles the energy transfers from distal to proximal links (from foot to thigh, and from shank to pelvis), in take-off phase-from proximal links to distal ones (from pelvis to shank, and from thigh to foot).     

The "two-headed" peptide inhibitors of interleukin-1 action

Two peptide fragments of IL-1 family proteins, ITGSE and VTKFYF compete with IL-1 for the cellular receptor. We synthesized a series of peptides composed of the sequences ITGSE and VTKFYK bound directly to each other or connected by such linkers as (Gly)(n), L- and D-Pro residues, Glu and Lys residues (with peptide bond formed by main amino and carboxy groups or by side chain groups), and beta-alanine and its homologues. Peptide IX with a gamma-Glu linker was the most potent inhibitor of IL-1 action. It was twice as potent as both of the peptides indicated.     

Dynamin: possible mechanism of "Pinchase" action.

Dynamin is a GTPase playing an essential role in ubiquitous intra cellular processes involving separation of vesicles from plasma membranes and membranes of cellular compartments. Recent experimental progress (. Cell. 93:1021-1029;. Cell. 94:131-141) has made it possible to attempt to understand the action of dynamin in physical terms. Dynamin molecules are shown to bind to a lipid membrane, to self-assemble into a helicoidal structure constricting the membrane into a tubule, and, as a result of GTP hydrolysis, to mediate fission of this tubule (). In a similar way, dynamin is supposed to mediate fission of a neck connecting an endocytic bud and the plasma membrane, i.e., to complete endocytosis. We suggest a mechanism of this "pinchase" action of dynamin. We propose that, as a result of GTP hydrolysis, dynamin undergoes a conformational change manifested in growth of the pitch of the dynamin helix. We show that this gives rise to a dramatic change of shape of the tubular membrane constricted inside the helix, resulting in a local tightening of the tubule, which is supposed to promote its fission. We treat this model in terms of competing elasticities of the dynamin helix and the tubular membrane and discuss the predictions of the model in relation to the previous views on the mechanism of dynamin action.     

Synergistic action of phorbol ester and IL-3 in the induction of "connective tissue-type" mast cell proliferation

12-O-Tetradecanoylphorbol-13-acetate (TPA), a tumor-promoting phorbol ester, induced the proliferation of connective tissue-type mast cells (CTMC) synergistically with IL-3 in a methylcellulose culture, as well as with IL-4. The culture of single CTMC and the serum-free culture of CTMC fractionated by Percoll density gradient centrifugation showed that this synergistic action of IL-3 and TPA required no effects of accessory cells or other humoral factors. Although the populations of CTMC acted on by TPA and IL-4 seemed to be close to each other, the velocity of colony growth induced by the simultaneous stimulation of the combination of TPA and IL-4 was faster than that induced by either TPA or IL-4 in the presence of IL-3. In addition, the addition of anti-IL-4 antibody did not neutralize the effect of TPA on the proliferation of CTMC. These results suggest that TPA and IL-4 act on the proliferation of CTMC synergistically with IL-3 via a different pathway. Beside TPA, other phorbol derivatives capable of activating protein kinase C (PKC) induced the proliferation of CTMC synergistically with IL-3, but phorbol derivatives which were unable to activate PKC did not. These results indicate that the activation of PKC is involved in the process of TPA action on the proliferation of CTMC. Furthermore, the facts that 1-oleoyl-2-acetylglycerol, which activated membrane PKC transiently, and staurosporine, which has been reported to inhibit PKC, did not induce the proliferation of CTMC in the presence of IL-3 and that the effect of TPA was exhibited by the sustained stimulation suggest that the action of TPA on the proliferation of CTMC requires at least two steps. The first one is the primary activation of membrane PKC and the second one is the disappearance of PKC from the cells, "down-regulation."