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PubMed1999

Cell-type-specific activation of p38 protein kinase cascades by the novel tumor promoter palytoxin.

Palytoxin is a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter. We used COS7 and HeLa cells to investigate the protein kinase cascades by which palytoxin activates the mitogen-activated protein kinase (MAPK) p38. Three p38 kinases have been identified: stress-activated protein kinase/extracellular signal-regulated kinase kinase-1 (SEK1), MAPK kinase 3 (MKK3), and MKK6. SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38. Although transiently overexpressed SEK1 activates p38 in cells, the importance of endogenous SEK1 for the activation of p38 by specific types of stimuli is unclear because some agents, such as sorbitol, can activate p38 in cells derived from SEK1 knockout mice. Because we previously showed that palytoxin activates JNK through an SEK1-dependent pathway, we investigated whether SEK1 also mediates the activation of p38 by palytoxin. The results presented here demonstrate that endogenous SEK1 does play an important role in the activation of p38 by palytoxin in specific cell types. In COS7 cells, palytoxin stimulated the phosphorylation of SEK1 and MKK6, and expression of dominant negative mutants of either SEK1 or MKK6 inhibited palytoxin-stimulated p38 activation. In HeLa cells, palytoxin stimulated the phosphorylation of MKK3 in addition to SEK1 and MKK6. In contrast to COS7 cells, in HeLa cells expression of a dominant negative mutant of SEK1 did not inhibit palytoxin-stimulated activation of p38, although expression of dominant negative mutants of either MKK3 or MKK6 did inhibit palytoxin-stimulated p38 activation in this cell type. These studies indicate that the importance of SEK1 in the activation of p38 by palytoxin depends on the ability of palytoxin to activate MKK3 and MKK6.

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PubMed2002

Extracellular signal-regulated kinase transmits palytoxin-stimulated signals leading to altered gene expression in mouse keratinocytes.

We have been probing the molecular mechanisms of tumor promoters that stimulate distinct initial signals to define critical downstream biochemical events in carcinogenesis. The action of the novel skin tumor promoter palytoxin on signaling and gene expression in keratinocytes, the primary target cells of tumor promoters, was therefore investigated. Palytoxin stimulated an increase in mRNA for matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis, in a keratinocyte cell line derived from initiated mouse skin (308). Palytoxin stimulated an increase in c-Fos binding to the activator protein-1 (AP-1) site present in the promoter of the mouse MMP-13 gene. This effect was specific because palytoxin had little effect on c-Jun, JunB, JunD, FosB, Fra-1, or Fra-2 binding or on overall levels of transcription factor binding. The increase in c-Fos binding corresponded to a palytoxin-stimulated increase in c-Fos protein levels. Palytoxin stimulated the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38. The MAPK kinase inhibitor PD 98059 blocked palytoxin-stimulated ERK activation. PD 98059 also blocked the palytoxin-stimulated increases in c-Fos protein levels, c-Fos binding to the AP-1 site, and MMP-13 mRNA. These studies identify important differences between palytoxin-stimulated signaling in keratinocytes derived from initiated mouse skin, the biologically relevant cell type, and other cell lines. Specifically, our data suggest that, in keratinocytes derived from initiated mouse skin, ERK plays an important role in transmitting palytoxin-stimulated signals to three downstream targets that are likely to affect carcinogenesis: c-Fos, AP-1, and MMP-13.

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PubMed1995

Involvement of the Na,K-ATPase in the induction of ion channels by palytoxin.

The effects of ouabain, ATP, and vanadate on palytoxin induction of ion channels were examined with the aim of elucidating the role of Na,K-ATPase in palytoxin action. Palytoxin-induced membrane depolarization of crayfish giant axons and single channel currents of frog erythrocytes and mouse neuroblastoma N1E-115 cells were examined using the intracellular microelectrode and patch-clamp techniques. External application of palytoxin in nanomolar concentrations induced depolarization in the crayfish giant axons, and the depolarization was inhibited by pretreatment of the axon with ouabain (10 microM). Internally perfused axons were less sensitive to palytoxin unless ATP (6 mM) was added internally. In patch-clamp experiments, picomolar palytoxin in the patch electrode induced single channels in both cell-attached and inside-out patches of erythrocytes and neuroblastoma cells. The induced channels had a conductance of about 10 pS, reversed near 0 mV in physiological saline solution, and was permeable to Na+, K+, Cs+, and NH4+, but not to choline. Single channel activities induced by palytoxin were inhibited by ouabain (10 microM) and vanadate (1 mM), but promoted by ATP (1 mM). The modulating effects of ouabain, vanadate, and ATP on palytoxin action suggest that the Na,K-ATPase is involved in the induction of single channels by palytoxin. Palytoxin-induced and ouabain-inhibitable single channels were observed in planar lipid bilayer incorporated with purified Na,K-ATPase. The results indicate that an interaction between palytoxin and Na,K-ATPase leads to opening of a 10-pS ion channel. They further raise the possibility that a channel structure may exist in the sodium pump which is uncovered by the action of palytoxin.

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PubMed1988

Palytoxin induces a nonselective cation channel in single ventricular cells of rat.

Palytoxin (PTX) causes a depolarization in every excitable tissue tested. We examined whether PTX induces a channel current, which might be responsible for the depolarizing action, in single ventricular cells from rat hearts using a patch-clamp technique. In cell-attached configuration, when PTX (30 pmol/l) was present in a patch pipette, a single channel current appeared, which was different from currents through known channels. When the major cation in the pipette was Na+, the amplitude of the unitary current at the resting potential level was 0.74 +/- 0.05 pA, the slope conductance was 9 pS and the reversal potential was 79 mV positive to the resting potential. The channel was little selective between cations because it was permeable not only to Na+ but also to K+, Cs+ and Li+ although it practically did not permit the passage of choline+, TEA+, Ba2+ and Ca2+. Thus PTX induces a novel, nonselective cation channel in cardiac cells, which may result in a depolarization.

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PubMed1982

Ouabain inhibits the increase due to palytoxin of cation permeability of erythrocytes.

1. Palytoxin in concentrations as low as 1 pM raises the potassium permeability of rat, human and sheep erythrocytes, and the sodium permeability of human erythrocytes. The release of potassium or sodium from human cells also occurs when extracellular sodium is replaced by choline. 2. Ouabain inhibits the release due to palytoxin of potassium ions from human, sheep and rat erythrocytes, and also the release of sodium ions from human cells. The glycoside effect is specific since a) it is already prominent with 5 X 10(-8) M ouabain b) rat erythrocytes are less sensitive than human cells to ouabain c) potassium release due to amphotericin B or the Ca2+ ionophore A 23187 is not influenced by ouabain and d) dog erythrocytes are resistant to palytoxin as well as to ouabain. 3. Palytoxin has no direct influence on the Na+, K+ - ATPase. It inhibits the binding of [3H]ouabain to erythrocyte membranes within the same concentration range as unlabelled ouabain. It partially displaces bound [3H]ouabain, and partially inhibits the inactivation of erythrocyte ATPase by the glycoside. Depletion of ATP or of external Ca2+ renders the cells less sensitive to palytoxin. Nevertheless inhibition by ouabain can be still demonstrated with human cells whose ATP stores had been largely exhausted, and also in the absence of external Ca2+. 4. Palytoxin decreases the surface tension at the air-water interface. We assume that the formation of nonspecific pores by palytoxin is linked with its surface activity. Further experiments should demonstrate whether ouabain prevents the binding of palytoxin to erythrocytes ("receptor hypothesis"), or whether an ouabain-sensitive hydrolysis of trace amounts of ATP ("metabolic hypothesis") promotes the palytoxin effect.

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PubMed1985

Characterization of depolarization induced by palytoxin and grayanotoxin-I in isolated cardiac tissues from dogs and guinea pigs.

The mode of depolarizing action of palytoxin (PTX) was compared with that of grayanotoxin-I (GTX-I) to examine the site of action of PTX in cardiac tissues isolated from dogs and guinea pigs: PTX at above 1 X 10(-10) mol/l depolarized the membrane of canine Purkinje fibres, canine and guinea-pig ventricular muscles regardless of stimulation. The PTX-induced depolarization was resistant to 1 X 10(-5) mol/l tetrodotoxin (TTX) but was attenuated by low Na medium. GTX-I at 1 X 10(-5) mol/l depolarized the membrane of ventricular muscles from dogs and guinea pigs only when they were stimulated. Although GTX-I caused depolarization in Purkinje fibres in both stimulated and rested conditions, the effect was greater in stimulated fibres. In the presence of GTX-I, ventricular muscles generated long-lasting action potentials as a response to stimuli. TTX antagonized the GTX-I-action. After treatment of PTX, GTX-I still induced the long-lasting action potential and TTX could antagonize it. Ouabain at 1 X 10(-6) or 3 X 10(-6) mol/l partially inhibited the PTX-induced depolarization in guinea-pig papillary muscles. The data suggest that the TTX-sensitive Na channel is intact after treatment with PTX and that PTX acts on a site different from the Na channel, possibly on the Na+, K+-ATPase in cardiac cells.

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PubMed1977

Effects of palytoxin on the electrical activity of dog and rabbit heart.

Reversible effects of palytoxin, extracted from colonies of the soft coral Palythoa caribaeorum, are described. There is a decrease of both membrane resting potential and overshoot during activity. Rise time of the action potential is prolonged, while repolarization is shortened. The electrical events resemble those seen with metabolic poisons.

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PubMed2001

Sanguinarine induces K+ outflow from yeast cells expressing mammalian sodium pumps.

Sanguinarine, an alkaloid from Sanguinaria canadensis, has no effect on the yeast Saccharomyces cerevisiae at concentrations of up to 225 microM. Yeast cells become sensitive to sanguinarine and lose cytosolic K+ in a time- and concentration-dependent manner when they express the mammalian Na+,K+-ATPase (sodium pump). Dose-response studies show that sanguinarine induces K+ outflow from cells expressing wild-type sodium pumps with an EC50 of 29.3+/-1.2 microM. A similar effect with a comparable EC50) of 26.8+/-1.3 microM is obtained with cells expressing an Asp369Ala mutant of the sodium pump alpha1 subunit. Since this sodium pump mutant does not hydrolyze ATP, it can be excluded that the observed sanguinarine-induced outflow of K+ is an active ion transport process. Ouabain inhibits the sanguinarine effect at concentrations higher than 1 mM. In contrast, proscillaridin A inhibits the sanguinarine-induced K+ outflow from cells expressing the wild-type sodium pump with an IC50 of 48.9+/-1.3 microM. A similar IC50 of 52.2+/-3.0 microM is obtained with cells expressing the Asp369Ala mutant. These data, together with the fact that sanguinarine inhibits the binding of [3H]ouabain to microsomes prepared from yeast cells expressing the sodium pump with an IC50 of 94.5+/-4.3 microM, all indicate that sanguinarine specifically targets the sodium pump, and that the observed K+ outflow is tightly associated with the presence of the enzyme.

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PubMed1998

Fatty acid composition of bacteria associated with the toxic dinoflagellate Ostreopsis lenticularis and with Caribbean Palythoa species.

The fatty acid composition of a Pseudomonas sp. (Alteromonas) and its host, the dinoflagellate Ostreopsis lenticularis, vectors in ciguatera fish poisoning, has been studied. The major fatty acids in O. lenticularis were 16:0, 20:5n-3, and 22:6n-3, but 18:2n-6, 18:3n-3, and 18:n-3 were also identified. In contrast to other dinoflagellates, 1 8:5n-3 was not detected in O. lenticularis. Even-chain fatty acids such as 9-16:1, 11-18:1, and 13-20:1 predominated in the Pseudomonas sp. from O. lenticularis, but 1 6-20% of (E)-11-methyl-12-octadecenoic acid was also identified. The chirality of the latter was confirmed by total synthesis (28% overall yield) starting from oxacyclotridecan-2-one. The fatty acid compositions of two other Pseudomonas species, from the palytoxin-producing zoanthids Palythoa mamillosa and P. caribdea, were also studied and were similar to that of the Pseudomonas sp. from O. lenticularis. The possibility of using some of these fatty acids as chemotaxonomic lipids in identifying marine animals that consume toxic dinoflagellates or zoanthids is discussed.

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PubMed1981

Delayed haemolytic action of palytoxin. General characteristics.

1. Palytoxin is a haemolysin. The erythrocytes from various species can be classified into a sensitive and a hardly sensitive group. The former contain potassium as their main inside cation and are arranged according to their sensitivity as hog greater than or equal to rat, mouse greater than rabbit greater than guinea-pig greater than man. The latter, comprising those from sheep and cattle, have sodium as their main inside cation. In addition, chicken erythrocytes are relatively insensitive. 2. Haemolysis of rat erythrocytes is preceded by a lag period of 1--2 h. With increasing temperature the haemolysis proceeds more quickly but reaches the same final range between 25 and 42 degrees C. The pH optimum in Britton-Robinson buffer supplemented with saline is between 7 and 8. Washing off palytoxin during the prelytic period reduces the haemolytic power. 3. The sensitivity of rat erythrocytes decreases with increase of osmolarity between 235 and 415 mosM. Accordingly, their osmotic resistance is lowered by palytoxin in a concentration-dependent manner. 4. With both rat and sheep erythrocytes, potassium loss by far precedes the haemolysis due to palytoxin. Potassium loss is measurable already after 1 min and increases with time. After 2 hours the quotient between the ED50 of haemolysis and that of potassium loss is around 200. Thus palytoxin is an unusually strong but slow haemolysin of the osmotic type. The extreme prelytic potassium loss and the correlation between susceptibility and potassium content of erythrocytes points towards the relevance of ionic fluxes.

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PubMed1982

Changes in erythrocyte permeability due to palytoxin as compared to amphotericin B.

Palytoxin causes within minutes a temperature-dependent K+ loss from human and rat erythrocytes which is followed within hours by haemolysis. It decreases the osmotic resistance in a concentration-dependent manner, so that osmotic influences are negligible for K+ release but considerable in haemolysis. External K+ inhibits the haemoglobin release and Rb+ inhibits the release of K+ and haemoglobin. Ca2+ (over 20 microM) and borate (over 5 microM) enhance the loss of K+ and haemoglobin. With both Ca2+ and borate present, the efficacy of palytoxin is raised about 10 000-fold. Under these conditions, about 15 palytoxin molecules per human cell trigger a 50% K+ loss over a wide range of cell concentrations. The palytoxin effect is reversible. After depletion from K+ by low concentrations of palytoxin, human cells can be refilled with K+ and resealed. The pores formed by palytoxin are small. They allow the entrance of Na+ and choline, whereas inositol is largely excluded and Ca2+, as well as sucrose and inulin, are completely excluded. Amphotericin B resembles palytoxin in its ability to cause a considerable prelytic K+ loss and to form small pores. However, it is about 1000-times weaker than palytoxin, is not inhibited by K+ or Rb+, is not activated by Ca2+ or borate, and has a negative temperature dependence. Thus palytoxin represents a novel type of cytolysin.

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PubMed1986

Involvement of (Na+ + K+)-ATPase in binding and actions of palytoxin on human erythrocytes.

Palytoxin (about 1 pM) increases the permeability of human erythrocytes. We now report its radiolabeling with 125I, followed by affinity purification on porcine kidney membranes. The resulting ligand binds fast and reversibly to intact erythrocytes. The Kd from velocity and equilibrium measurements is 2 X 10(-11) M, and the number of binding sites about 200 per cell. Binding is promoted by divalent cations (Ca2+ greater than Sr2+ greater than Ba2+) and by borate. It is inhibited by K+ (IC50 2 mM), ouabain (IC50 3 X 10(-9) M) and ouabagenin (IC50 6 X 10(-6) M). Conversely, [3H]ouabain is displaced by the substances and concentrations mentioned, and also by palytoxin (Ki 3 X 10(-11) M). Dog erythrocytes, which are known to possess a very low (Na+ + K+)-ATPase activity, are resistant to and lack specific binding sites for palytoxin. Binding of 125I-palytoxin, like that of [3H]ouabain, depends on the state of (Na+ + K+)-ATPase. ATP depletion decreases binding of both ligands to erythrocytes. Binding of 125I-palytoxin and [3H]ouabain to red cell stroma is partially restored by ATP. In contrast to [3H]ouabain, binding of 125I-palytoxin to red cell stroma is not promoted by Mg2+ and Pi. The data show that (a) all known promoters and inhibitors of palytoxin action on human red cells do so by enhancing or decreasing its binding, (b) (Na+ + K+)-ATPase serves as a receptor for palytoxin, and (c) the antagonism by ouabain is competitive at the receptor level. They support our previous hypothesis that palytoxin increases human erythrocyte permeability by formation of pores through (Na+ + K+)-ATPase or its close vicinity.

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PubMed1994

Inhibition of the actions of palytoxin on the K+ efflux from red cells and on the Na/K-ATPase activity by a monoclonal antibody.

Palytoxin (PTX) binds to the Na/K pump, inhibits the (Na/K)-ATPase and forms Na and K permeable channels in human red cells. Here, we report that a monoclonal antibody raised against a derivative of PTX (Bignami, G.S. et al. (1992) Toxicon 30, 687-700) inhibits these effects. The observations are consistent with a model in which (a) the antibody binds and, thus reduces the concentration of free PTX available to react with the Na/K pump, and, (b) the PTX-antibody complex also binds to the PTX receptor on the Na/K pump but in such a way that a cation permeable channel is not formed, probably by reducing the concentration of free PTX. Using this model, we estimate that the apparent dissociation constant for the binding of PTX to antibody is 0.2 nM.

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PubMed1994

Inhibition by ouabain of palytoxin-induced catecholamine secretion and calcium influx into cultured bovine adrenal chromaffin cells.

The effect of ouabain on palytoxin (PTX)-induced catecholamine secretion from cultured bovine adrenal chromaffin cells was examined in relation to its effect on calcium (Ca2+) influx into the cells. Ouabain showed concentration-dependent inhibition of catecholamine secretion induced by PTX. Ouabain also inhibited [45Ca]2+ influx induced by PTX, this inhibition being parallel with that of catecholamine secretion. The inhibitory effects of ouabain on PTX-induced catecholamine secretion and [45Ca]2+ influx were both overcome by increasing the concentrations of PTX, indicating that ouabain inhibited the actions of PTX in a competitive manner. These results suggest that the ouabain-sensitive (or-binding) site on the cell membrane might be the target site of action of PTX, which causes an increase in Ca2+ permeability and initiation of catecholamine secretion.

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