The physical feature of the G‐F transformation of action caused by a small amount of magnesium ions was investigated by measuring flow birefringence, light scattering, viscosity, and sedimentation of action solutions at various concentrations of actin and magnesium ions. All experimental results indicate that the G‐F transformation of actin can be regarded as a reversible fibrous condensation. When the concentration of actin is increased at a constant concentration of magnesium ions, fibrous aggregates of actin molecules, F‐actins, can be formed only above a critical actin concentration which is determined by the condition of medium and decreases rapidly with increasing concentration of magnesium ions. Above the critical concentration, all of the excess active actin molecules are transformed into F‐actins. These F‐actins are coexisting with active (G‐)actin molecules, the concentration of which is independent of the concentration of F‐actin and equal to the concentration of active actin at the critical point. The state of apparent units of F‐actins in solution is also determined by the condition of medium and independent of the concentration. With increasing concentration of magnesium ions, the apparent units of F‐actin become longer and longer and their thickness increases. Small globular aggregates are always observed below the critical point of formation of long fibrous aggregates. These experimental results show qualitative agreement with theoretical results obtained by one of the authors on fibrous and globular aggregations of charged macromolecules.

No abstract

In the sense that they activate the 25" Ca*+-adenosine-5'-triphosphatase, inhibit the 25" Ca*+inosine-5'-triphosphatase, and inhibit the 0' activity of both nucleosidetriphosphatases, dioxane and hydrogen peroxide are true "modifiers" of myosin nucleosidetriphosphatase. Modification by peroxide, as by p-mercuribenzoate, clearly involves reaction of certain myosin sulfhydryl groups, but no compelling evidence for sulfhydryl involvement was found in modification by dioxane, and there was found some direct evidence against sulfhydryl involvement in modification by 2,Cdinitrophenol. On the other hand, the groups on the myosin molecule directly responsible for either activating or inhibiting phases of "modification" are probably the same for all modifiers. This hypothesis, expressed quantitatively in a stochastic model, was afbmatively tested in the case of p-mercuribenzoate and 2,4-dinitrophenol. It was found incidentally that histidine protects against modification which involves oxidation because histidine itself is easily oxidized in a reaction involving its amino group.We are concerned in this paper with interpreting experiments in which the nucleosidetriphosphatase activity of CaZ+-myosin is modified by various reagents. Such an objective presumes that the activity of unmodified enzyme is understood, and this is not really the case. However, as a result of the work of many laboratories, there is a hypothesis about unmodified and modified myosin catalysis into which many observations seem to fit, and it is useful to state this hypothesis at the outset and in some degree to justify it a posteriori.A Hypothesis about Myosin Nucleosidetriphosphatase. -In most experiments with substrate-saturated and Ca*+-saturated myosin, the substrate is ATP, the temperature is ea. 25', and the p H is near neutral. These conditions have come to define the "normal" or reference behavior of the enzyme, and one can discuss consequences of changing conditions; for example, at 25" a partial titration of the sulfhydryl content activates ATPase and inhibits ITPase,' but at 0" the same titration inhibits both. We (see Gilmour, 1960;Morales and Hotta, 1960) have felt it helpful to focus on more general properties of the enzyme and of the reagents which affect it. In our terms, the crucial properties of myosin catalysis are as follows (see also Figs. 1 and 2).

In humans, the administration of phencyclidine causes schizophrenic-like symptoms that persist for several weeks after withdrawal from phencyclidine use. We demonstrated here that mice pretreated with phencyclidine (10 mg/kg/day s.c. for 14 days) showed an enduring impairment of associative in a Pavlovian fear conditioning 8 days after cessation of phencyclidine treatment. Extracellular signaling-regulated kinase (ERK) was transiently activated in the amygdalae and hippocampi of saline-treated mice after conditioning. In the phencyclidine-treated mice, the basal level of ERK activation was elevated in the hippocampus, whereas the activation was impaired in the amygdala and hippocampus after conditioning. Exogenous N-methyl-D-aspartate (NMDA), glycine, and spermidine-induced ERK activation was not observed in slices of hippocampus and amygdala prepared from phencyclidine-treated mice. Repeated olanzapine (3 mg/kg/day p.o. for 7 days), but not haloperidol (1 mg/kg/day p.o. for 7 days), treatment reversed the impairment of associative learning and of fear conditioning-induced ERK activation in repeated phencyclidine-treated mice. Our findings suggest an involvement of abnormal ERK signaling via NMDA receptors in repeated phencyclidine treatment-induced cognitive dysfunction. Furthermore, our phencyclidine-treated mice would be a useful model for studying the effect of antipsychotics on cognitive dysfunction in schizophrenia.

No abstract