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At least 19 recordsLinked to original sources
PubMed1981

The effects of cytochalasins on lymphocytes. Identification of distinct cytochalasin-binding sites in relation to mitogenic response and hexose transport.

Cytochalasin B inhibits phytomitogen-induced human lymphocyte proliferation with a Ki of approximately 6 X 10(-6) M. Cytochalasins A, C, D, E, and H are also inhibitory with varying degrees of potency, whereas cytochalasin G and chaetoglobosins A, B, C, E, F, and J are not at concentrations as high as 15 microM. Cytochalasin B also competitively inhibits carrier-mediated equilibrium exchange of hexose (Ki of approximately 7 X 10(-7) M), but cytochalasin E is ineffective. Cytochalasin B binds reversibly to the lymphocyte at three distinct sites: L, M, and H. The ligand binding at L site shows the apparent dissociation constant (Kd) of 1 to 3 X 10(-6) M and total binding sites (Bt) of 6 to 8 X 10(7)/cell, represents approximately 85% of the total saturable binding, displays a broad specificity interacting with cytochalasins C, D, and E, is not displaceable by D-glucose, is located mostly in a cytosol fraction, and exists in intimate relation to cytoskeletal actin. M site shows a Kd of 2 to 4 X 10(-7) M and Bt of 5 to 8 X 10(6)/cell, represents about 8% of the total saturable binding, shows stringent specificity not being displaced by cytochalasins C, D, and E, is competitively displaced by D-glucose and phloretin, and is quantitatively recoverable in the plasma membrane fraction. The binding to H site shows a Kd of 0.5 to 1.0 X 10(-7) M and Bt of 4 to 5 X 10(6)/cell, representing approximately 7% of the total saturable binding, shows a broad specificity, is insensitive to D-glucose, and is membrane bound. It is proposed that L site is actin and is involved in the inhibition of lymphocyte mitogenesis, whereas M site is associated with the hexose transport carrier. Structure-activity relationships of cytochalasin effects are also discussed.

Binding Sites↗
PubMed1984

Effects of cytochalasins on lymphocytes: some distinctive features of cytochalasin-E.

Cytochalasin-E (CE) has specific properties that distinguishes it from other cytochalasin congeners. We have taken advantage of these in investigating the mechanisms operative in the effects of cytochalasins on lymphocyte proliferative responses to phytomitogens. Like the other cytochalasins, CE inhibits these responses only when present during the early phases of exposure of lymphocytes to mitogens, but not when added later on. The effects of CE are irreversible since prior incubation of lymphocyte in CE renders them incapable of response. Unlike the effects of cytochalasin A, the only other irreversibly active congener, lymphocytes preincubated in CE completely recover the ability to respond if they are cultured in cytochalasin-free medium for 48 hours. Unlike cytochalasins A and B, cytochalasin-E does not inhibit glucose transport into lymphocytes and all. We have shown that human lymphocytes bind cytochalasins at 3 distinct classes of sites named L, M, and H (J. Biol. Chem. 256:1290-1300, 1981). CE binds irreversibly to the L and H-sites on the short to medium term but does not bind to the glucose displaceable M-site at all. CE may have potential usefulness as affinity label towards isolation of specific binding sites since the chemical structure offers feasible approaches towards isotopic labelling.

Cytochalasins↗
PubMed1988

Actin assembly activity of cytochalasins and cytochalasin analogs assayed using fluorescence photobleaching recovery.

The effects on actin self-assembly of 9 common cytochalasins and 9 synthetic analogs have been assayed using fluorescence photobleaching recovery (FPR). The specific assembly activities of cytochalasins determined by this assay are (i) reduction of the fraction of actin molecules incorporated into filaments; (ii) increase of the steady-state diffusion coefficients of filaments, from which filaments shortening may be inferred; and (iii) acceleration of the initial rate of assembly. Of the compounds studied, only cytochalasin D shows strong activity of all three types. The range of activities shown by other compounds indicates clearly that these three activity types are distinct and independent. Inspection of the molecular structures of these 18 compounds for correlation of structure and activity reveals that the three different activities depend on distinct structural features. The Mg2+ dependence of filament-shortening activity by certain cytochalasins may be explained by the Mg2+ chelating ability of two suitably positioned oxygen atoms on the convex face of the bicyclic isoindolone system. Inhibition of filament elongation may involve very specific, high-affinity cytochalasin interactions at a binding site on terminal actin molecules, while accelerating activity may occur by weaker, less specific binding interactions of cytochalasins with monomeric actin.

Actin Cytoskeleton↗
PubMed1984

Observations on the effects of cytochalasin B and cytochalasin D on ADP- and chymotrypsin-treated platelets.

Cytochalasin B has been reported to inhibit fibrinogen binding and aggregation of rabbit platelets in response to ADP. The present study was designed to ascertain whether cytochalasins B and D inhibit aggregation by interfering with the exposure of fibrinogen receptors or more directly by inhibiting binding to available receptors. Aspirin-treated, washed, human platelets stimulated with ADP or chymotrypsin were used for these studies. Neither cytochalasin B nor D significantly inhibited the binding of fibrinogen to chymotrypsin-treated platelets when these agents were added to platelet suspensions before (16 +/- 8% (mean +/- SD) inhibition, N = 8), or after (15 +/- 10% inhibition, N = 13) chymotrypsin treatment, i.e., before or after fibrinogen receptor exposure. This apparent lack of cytoskeletal involvement was consistent with the observation that chymotrypsin-treated platelets were unable to retract reptilase-induced fibrin clots, an activity that was restored by adding ADP. In contrast, incubating platelets with either cytochalasin B or D for 30 min before or after stimulation with ADP decreased fibrinogen binding by 42 +/- 16% (N = 13) and 27 +/- 11% (N = 8), respectively, compared to DMSO-treated controls. Platelets stimulated with ADP and incubated with DMSO for 30 min, however, became refractory and aggregated poorly in response to a second dose of ADP. In comparison, platelets stimulated with ADP, but incubated with cytochalasin B or D, aggregated more extensively when stimulated by a second dose of ADP despite diminished fibrinogen binding. The data suggest (1) microfilament polymerization is important not only for the exposure of fibrinogen receptors by ADP, but also for preserving the ability of exposed receptors to bind fibrinogen, (2) exposure of fibrinogen receptors by chymotrypsin is not accompanied by significant cytoskeletal activation, and (3) cytochalasins may impart partial protective effects against the development of ADP-induced refractoriness.

Adenosine Diphosphate↗
PubMed1980

Cytochalasin B and the structure of actin gels. II. Further evidence for the splitting of F-actin by cytochalasin B.

Cytochalasin B decreased the flow birefringence and s20,w and increased the extinction angle of actin filaments in salt solutions favoring polymerization of the protein. These changes occurred without a detectable increase in the equilibrium actin monomer concentration determined by a radioassay. These results complement earlier observations indicating that cytochalasin B shortens actin filaments without net depolymerization. Analyzed in terms of Flory's classical network theory, this shortening accounts for the marked effect of cytochalasin B in dissolving the gel structure of F-actin crosslinked by actin-binding protein concentrations near the critical concentration for incipient gelation. Cytochalasin B decreased the annealing rate of low concentrations of actin filament fragments prepared by sonic disruption. The result is consistent with the idea that cytochalasin B binds to the ends of actin filaments, and may explain how cytochalasin B causes filament shortening.

Actins↗
PubMed1980

Structure of cytochalasins and cytochalasin B binding sites in human erythrocyte membranes.

Twenty cytochalasins were tested for binding to and for inhibition of glucose transport in human erythrocyte membrane. In this membrane three cytochalasin B (CB) binding sites have been identified. All but three of the cytochalasins bind at site II. On the other hand, only nine of them, which are structurally closely related, bind at site I and inhibit glucose transport. For site I (and site III) binding and glucose transport inhibitory activities (a) the macrocyclic ring in the cytochalasin molecule must be at least 13-membered, (b) the nature of the aromatic ring at C-10 is not important, (c) the C-20-C-23 region makes a major contribution, and (d) the C-5-C-7 segment has a relatively minor influence. These findings do not support a proposed mechanism which involves 24, C-23, C-20, and C-1 oxygen atoms for interaction of CB with glucose carrier. The structural requirements for site II activity are less stringent. The size and the structure of the macrocyclic ring and the nature of the aromatic residue at C-10 modulate this activity only slightly, if at all. Modifications in the C-5-C-7 region of the molecule, however, result in substantial changes in this activity.

Binding, Competitive↗
PubMed1977

The binding sites of cytochalasin D. II. Their relationship to hexose transport and to cytochalasin B.

Cytochalasin B (CB) was able to compete with tritiated cytochalasin D (3H-CD) for binding sites in HEp-2 cells. The pattern of inhibition suggested that CB associates with a low affinity class of CD binding sites. Glucose and maltose did not inhibit binding of 3H-CD to isolated HEp-2 plasma membrane. Inhibition of hexose transport by CD was negligible, but CD did not block the potent inhibition of this transport by CB. These results indicate that CD does not bind to the high affinity CB receptor reportedly associated with the hexose transport system, and that this receptor cannot mediate the morphological effects of CD. Both CD and CB induced contraction-zeoisis in HEp-2 cells; CB was less potent than CD, and their effects appeared to be additive. It was concluded that the high affinity binding sites for CD and CB are different, but that these congeners share a low affinity site. Both high and low affinity sites for CD appear to mediate its morphological effects; only the low affinity class appears to be involved for CB. Possible identification of the common low affinity binding site as actomyosin (detailed in Tannenbaum et al., '77) is further discussed.

Binding Sites↗
PubMed1981

Effects of cytochalasin B on actin and myosin association with particle binding sites in mouse macrophages: implications with regard to the mechanism of action of the cytochalasins.

The intracellular distribution of F-actin and myosin has been examined in mouse peritoneal macrophages by immunofluorescence microscopy. In resting, adherent cells, F-actin was distributed in a fine networklike pattern throughout the cytoplasm. Myosin, in contrast, was distributed in a punctate pattern. After treatment with cytochalasin B (CB), both proteins showed a coarse punctate pattern consistent with a condensation of protein around specific foci. After CB-pretreated cells were exposed to opsonized zymosan particles, immunofluorescent staining for F-actin and myosin showed an increased staining under particle binding sites. Transmission electron microscope (TEM) examination of whole-cell mounts of such preparations revealed a dense zone of filaments beneath the relatively electron-translucent zymosan particles. At sites where particles had detached during processing, these filament-rich areas were more clearly delineated. At such sites dense arrays of filaments that appeared more or less randomly oriented were apparent. The filaments could be decorated with heavy meromyosin, suggesting that they were composed, in part, of F-actin and were therefore identical to the structures giving rise to the immunofluorescence patterns. After viewing CB-treated preparations by whole-mount TEM, we examined the cells by scanning electron microscopy (SEM). Direct SEM comparison of the filament-rich zones seen by TEM showed that these structures resulted from the formation of short lamellipodial protrusions below the site of particle binding. Electron micrographs of thin-sectioned material established that these lamellipodial protrusions were densely packed with microfilaments that were in part associated with the cytoplasmic surface of the plasma membrane. The formation of particle-associated lamellipodia did not appear to represent merely a slower rate of ingestion in the presence of CB, because they formed within minutes of particle contact with the cell membrane and were not followed by particle ingestion even after a 1-h or longer incubation. Furthermore, their formation required cellular energy. These results suggest that cytochalasin B blocks phagocytosis of large particles by affecting the distances over which any putative actomyosin-mediated forces are generated.

Actins↗
PubMed1990

The effects of cytochalasins on lymphocytes: V. Interaction of trifluoperazine and cytochalasin B in inhibition of human lymphocyte proliferation.

Trifluoperazine (TFP), a phenothiazine derivative, is known to inhibit calmodulin-mediated phenomena. We report here that TFP reversibly inhibited lymphocyte proliferative responses to mitogenic lectins. This inhibition was observed only when TFP was added during the early stages of exposure of lymphocytes to the stimulus. Furthermore, at suboptimally inhibitory concentrations of each compound, effects of TFP on lymphocyte proliferation were additive to those of cytochalasin B (CB). Incubation of lymphocytes in TFP (10(-5)-10(-4) M) markedly inhibited cytochalasin B binding to the actin associated, low affinity binding site without affecting its binding to the high affinity site or to the medium affinity site. This effect developed gradually during incubation with TFP, becoming demonstrable after 30 minutes reaching maximum after 30-60 min of incubation at 37 degrees. The findings suggest the occurrence of an interaction of TFP with the lymphocyte cytoskeleton, which may play a role in the impairment in the transmission of the mitogenic signal.

Binding Sites↗
PubMed1982

Structure-activity correlations of cytochalasins. Novel halogenated and related cytochalasin C and D derivatives.

A series of halogenated and related analogues of cytochalasin C (CC) and D (CD) has been synthesized, and the biological activities of the analogues as inhibitors in a cell-free contractility model system obtained from Ehrlich ascites tumor cells were evaluated. The reaction sequence involved treatment of CD with phenyltrimethylammonium perbromide to give 6,12-dibromo-CD (2), dehydrohalogenation of 2 to 12-bromo-CC (3), and the subsequent conversions of 3 to 12-azido- (4), 12-iodo- (5), and 12-cyano-CC (6). The ID50 values for 5, 3, 4, 2, and 6 are 6.0, 7.4, 8.8, 45, and 77 X 10(-7) M, respectively, in comparison to ca. 2.8 X 10(-7) M for the parental compounds. The potential cell and molecular biological applications of these compounds are delineated.

Animals↗