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PubMed2003

Ion occlusion/deocclusion partial reactions in individual palytoxin-modified Na/K pumps.

In P-type ion-motive ATPases, transported ions approach their binding sites from one membrane surface, become buried deep within "occluded" conformations in which the sites are inaccessible from either membrane side, and are then deoccluded and released to the opposite membrane surface. This describes an alternating-gate transport mechanism, in which the pump acts like an ion channel with two gates that open and close alternately. The occluded states ensure that one gate closes before the other can open, thus preventing the large electrodiffusive ion fluxes that would otherwise quickly undo the pump's electrochemical work. High-resolution crystal structures of two conformations of the SERCA (sarcoplasmic and endoplasmic reticulum Ca(2+)) P-type ATPase, together with mutagenesis results and analyses of structural models based on homology, have begun to provide a picture of the ion coordination sites in related P-type ATPases, including the Na/K pump. However, in no P-type ATPase are the structures and mechanisms of the gates known. The marine toxin, palytoxin (PTX), is known to bind to the Na/K pump and elicit a nonselective cation leak pathway, possibly by disrupting the strict coupling between the pump's inner and outer gates, allowing them to both be open. We recently found that ion flow through PTX-modified Na/K pump-channels appears to be modulated by two gates that can be regulated by the pump's physiological ligands in a manner suggesting that gating reflects underlying ion occlusion/deocclusion partial reactions. We review that work here and provide evidence that the pore of the PTX-induced pump-channel has a diameter > 6 A.

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PubMed2002

Action of palytoxin on apical H+/K+-ATPase in rat colon.

Palytoxin stimulated a cation-dependent short-circuit current (Isc) in rat distal and proximal colon in a concentration-dependent fashion when applied to the mucosal surface of the tissue. The distal colon exhibited a higher sensitivity to the toxin. The palytoxin-induced Isc was blocked by vanadate but was resistant to ouabain or scilliroside, suggesting the conversion of a vanadate-sensitive H+/K+-ATPase into an electrogenic cation transporter. Cation substitution experiments with basolaterally depolarized tissues suggested an apparent permeability of the palytoxin-induced conductance of Na+>K+>Li+. Immunohistochemical control experiments confirmed the absence of the Na+/K+-ATPase in the apical membrane. Consequently, the pore-forming action of palytoxin is not restricted to Na+/K+-ATPase but is also observed with the colonic H+/K+-ATPase.

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PubMed1989

Effect of palytoxin on the calcium current and the mechanical activity of frog heart muscle.

1. The effect of palytoxin (PTX) on the Ca current (ICa) and the mechanical activity of frog atrial fibres was studied by use of the double sucrose gap voltage clamp technique. 2. In normal Ringer solution, PTX transiently increased the electrically-evoked peak tension which then decreased while a major contracture developed. PTX slowed the time course of the relaxation phase of the evoked tension. 3. Evidence is presented which suggests that the toxin also increased the entry of Ca and Sr via the Na-Ca exchange mechanism. It also induced the development of a Ca-dependent outward current which was inhibited by Sr. 4. In Na-free solution, PTX increased ICa and shifted the reversal potential for Ca towards more negative membrane potentials, thus suggesting that the internal Ca concentration had increased. Current-voltage, tension-voltage, time to peak-voltage and inactivation time constant-membrane potential curves were all shifted towards more negative membrane potentials in the presence of PTX. 5. These effects of PTX are similar to those caused by the increase in internal Ca concentration induced by Na ionophores by way of voltage-dependent Ca influx of the Na-Ca exchange mechanism.

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PubMed1991

Palytoxin: a potent stimulator of catecholamine release from cultured bovine adrenal chromaffin cells.

The effect of palytoxin (PTX), a potent marine toxin, on catecholamine release from cultured bovine adrenal chromaffin cells was examined. PTX at concentrations of over 10(-9) M induced catecholamine release dose-dependently. About 40-50% of the total cellular catecholamine was released during 20-min incubation with 3 x 10(-8) M PTX. PTX-induced catecholamine release was dependent on both extracellular Na+ and Ca2+, and was inhibited by organic and inorganic Ca2+ channel blockers, but not by tetrodotoxin. PTX-induced increase in 45Ca2+ influx into the cells, which was associated with catecholamine release, was also inhibited by these Ca2+ channel blockers. These results indicated that PTX-induced catecholamine release was mediated by activation of Na(+)-dependent, tetrodotoxin (TTX) insensitive voltage-dependent Ca2+ channels.

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PubMed2006

Ion permeation through the Na+,K+-ATPase.

P-type ATPase pumps generate concentration gradients of cations across membranes in nearly all cells. They provide a polar transmembrane pathway, to which access is strictly controlled by coupled gates that are constrained to open alternately, thereby enabling thermodynamically uphill ion transport (for example, see ref. 1). Here we examine the ion pathway through the Na+,K+-ATPase, a representative P-type pump, after uncoupling its extra- and intracellular gates with the marine toxin palytoxin. We use small hydrophilic thiol-specific reagents as extracellular probes and we monitor their reactions, and the consequences, with cysteine residues introduced along the anticipated cation pathway through the pump. The distinct effects of differently charged reagents indicate that a wide outer vestibule penetrates deep into the Na+,K+-ATPase, where the pathway narrows and leads to a charge-selectivity filter. Acidic residues in this region, which are conserved to coordinate pumped ions, allow the approach of cations but exclude anions. Reversing the charge at just one of those positions converts the pathway from cation selective to anion selective. Close structural homology among the catalytic subunits of Ca2+-, Na+,K+- and H+,K+-ATPases argues that their extracytosolic cation exchange pathways all share these physical characteristics.

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PubMed1982

Effects of palytoxin on sodium and potassium permeabilities in unmyelinated axons.

Palytoxin (PTX) is a very potent marine toxin isolated from the Zoanthid Palythoa. Its effects on the nerve membrane have been studied on two different preparations: the giant axon of the Cockroach, Periplaneta americana and the giant axon of the Squids, Loligo pealei and Loligo forbesi. In both preparations, PTX at concentrations ranging from 0.03 to 10 microM depolarized the axonal membrane through a selective increase in the resting sodium conductance. This increase was never reversible and was only temporarily and partly antagonized by tetrodotoxin (TTX) at concentrations which block completely the voltage-dependent sodium conductance. A voltage-clamp analysis of these effects showed that, besides this increase, PTX induced complex modifications of the voltage-dependent ionic conductances and increased the leak conductance. The selectivity of the PTX induced sodium channels seemed to decrease with time. Altogether, the results indicate that PTX induces strong and irreversible modifications of the membrane structure.

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PubMed2004

Palytoxin disrupts cardiac excitation-contraction coupling through interactions with P-type ion pumps.

Palytoxin is a coral toxin that seriously impairs heart function, but its effects on excitation-contraction (E-C) coupling have remained elusive. Therefore, we studied the effects of palytoxin on mechanisms involved in atrial E-C coupling. In field-stimulated cat atrial myocytes, palytoxin caused elevation of diastolic intracellular Ca(2+) concentration ([Ca(2+)](i)), a decrease in [Ca(2+)](i) transient amplitude, Ca(2+) alternans followed by [Ca(2+)](i) waves, and failures of Ca(2+) release. The decrease in [Ca(2+)](i) transient amplitude occurred despite high sarcoplasmic reticulum (SR) Ca(2+) load. In voltage-clamped myocytes, palytoxin induced a current with a linear current-voltage relationship (reversal potential approximately 5 mV) that was blocked by ouabain. Whole cell Ca(2+) current and ryanodine receptor Ca(2+) release channel function remained unaffected by the toxin. However, palytoxin significantly reduced Ca(2+) pumping of isolated SR vesicles. In current-clamped myocytes stimulated at 1 Hz, palytoxin induced a depolarization of the resting membrane potential that was accompanied by delayed afterdepolarizations. No major changes of action potential configuration were observed. The results demonstrate that palytoxin interferes with the function of the sarcolemmal Na(+)-K(+) pump and the SR Ca(2+) pump. The suggested mode of palytoxin toxicity in the atrium involves the conversion of Na(+)-K(+) pumps into nonselective cation channels as a primary event followed by depolarization, Na(+) accumulation, and Ca(2+) overload, which, in turn, causes arrhythmogenic [Ca(2+)](i) waves and delayed afterdepolarizations.

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PubMed2002

Na+/K+-pump ligands modulate gating of palytoxin-induced ion channels.

The Na+/K+ pump is a ubiquitous P-type ATPase that binds three cytoplasmic Na+ ions deep within its core where they are temporarily occluded before being released to the extracellular surface. The 3Na+/2K+ -exchange transport cycle is completed when two extracellular K+ ions bind and become temporarily occluded within the protein and subsequently released to the cytoplasm. Coupling of Na+ -ion occlusion to phosphorylation of the pump by ATP and of K+ -ion occlusion to its dephosphorylation ensure the vectorial nature of net transport. The occluded-ion conformations, with binding sites inaccessible from either side, represent intermediate states in these alternating-access descriptions of transport. They afford protection against potentially catastrophic effects of inadvertently allowing simultaneous access from both membrane sides. The marine toxin, palytoxin, converts Na+/K+ pumps into nonselective cation channels, possibly by disrupting the normal strict coupling between opening of one access pathway in the Na+/K+ ATPase and closing of the other. We show here that gating of the channels in palytoxin-bound Na+/K+ pumps in excised membrane patches is modulated by the pump's physiological ligands: cytoplasmic application of ATP promotes opening of the channels, and extracellular replacement of Na+ ions by K+ ions promotes closing of the channels. This suggests that, despite the presence of bound palytoxin, certain partial reactions of the normal Na+/K+ -transport cycle persist and remain capable of effecting the conformational changes that control access to the pump's cation-binding sites. These findings affirm the alternating-access model of ion pumps and offer the possibility of examining ion occlusion/deocclusion reactions in single pump molecules.

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PubMed1989

Palytoxin acts through Na+,K+-ATPase.

Palytoxin is the most potent animal toxin, with a unique structure. The author's group has searched for its mode of action with the following results: 1. Palytoxin (1 pM and less) causes a fast K+ outflow from erythrocytes; 2. Extracellular Ca2+ and borate, and intracellular ATP enhance, but ouabain potently inhibits the palytoxin effects; 3. Palytoxin increases the permeability for Na+ and K+ but not for Ca2+; 4. Palytoxin in comparatively high concentrations (100 nM and above) inhibits Na+,K+-ATPase; 5. Palytoxin can be radiolabeled with 125I. Its receptor is very similar to, but not identical to that of ouabain. A reaction scheme has been delineated which allows an explanation to be obtained for all the known actions of palytoxin. It centers on the hypothesis that palytoxin binds to Na+,K+-ATPase and converts the enzyme or its close vicinity into an open channel with the permselectivity measured on erythrocytes. Patch clamp data from myocytes were obtained in other laboratories. They prove the presence of the predicted palytoxin channel.

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PubMed2006

Production of 7-epi-pectenotoxin-2 seco acid and assessment of its acute toxicity to mice.

Pectenotoxins (PTXs) accumulate in shellfish feeding on dinoflagellates of the genus Dinophysis, so that humans can be exposed to these toxins through shellfish consumption. Some PTXs are toxic to experimental animals, whereas others are of much lower toxicity. Pectenotoxin-2, the most abundant PTX from most Dinophysis spp., is rapidly metabolized by most shellfish to a mixture of pectenotoxin-2 seco acid (2) and 7-epi-pectenotoxin-2 seco acid (1). A mixture of 1 and 2 was produced during purification of an extract from in vitro enzymatic hydrolysis of pectenotoxin-2. These were separated by preparative HPLC, and the structure of 1 was confirmed by one- and two-dimensional 1H and 13C NMR spectroscopy and LC-MS3 analyses. No toxic changes were recorded in mice injected intraperitoneally with 1 or 2 at a dose of 5000 microg/kg. PTX seco acids are therefore unlikely to be of consequence to human consumers at the concentrations found in contaminated shellfish.

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PubMedDate not supplied

Na,K-ATPase characterized in artificial membranes. 2. Successive measurement of ATP-driven Rb-accumulation, ouabain-blocked Rb-flux and palytoxin-induced Rb-efflux.

The Na,K-ATPase is a multifunctional system anchored in the membrane of eukaryotic cells; it is responsible for the establishment and regulation of the Na/K balance of cell and organism by a stoichiometric mechanism linking Na extrusion to K uptake and ATP hydrolysis. The receptor for cardioactive steroids such as digoxin and ouabain is located at the extracellular surface of the system. Conversely, palytoxin, the most potent animal toxin, exerts its toxic effect by creating nonspecific leaks in the cell membrane leading to K-efflux and influx of Na and Ca ions. Ouabain prevents the pore-forming action of palytoxin in cells and therefore Na,K-ATPase is suspected to be the common receptor of ouabain and palytoxin. We have developed an artificial membrane system to determine structure-function relationships and ligand interactions of purified Na,K-ATPase: two-sided, bi-directional ATP-filled liposomes. In this system, ATP-driven 86Rb accumulation, arrest of 86Rb-uptake by ouabain, and palytoxin-induced 86Rb-leak were measured successively in the same preparation. Ouabain prevented the leak when the enzyme was ouabain-sensitive (rabbit kidney) but not when it was ouabain-resistant (rat kidney). On the basis of these data in conjunction with conformational analyses, allosteric conformational competition for the ouabain-palytoxin antagonism is proposed.

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PubMed1995

Lophozozymus pictor toxin: a fluorescent structural isomer of palytoxin.

Purified Lophozozymus pictor toxin (LPTX) shares many properties similar to palytoxin (PTX). LPTX and palytoxin isolated from Palythoa caribaeorum (C-PTX) have similar mol. wts of approx. 2680 on ionspray mass spectrometry (MS). In addition, antibodies against PTX could recognize and bind LPTX. Mixed mode high-performance liquid chromatography (HPLC) of LPTX, C-PTX and H-PTX (isolated from Palythoa tuberculosa) showed a major PTX component common to all three with the characteristic PTX-like UV spectrum at a retention time (Rt) of 17 min. However, LPTX exhibits fluorescence but PTX of equivalent toxicity does not. LPTX showed a unique peak at Rt of approx. 22 min on mixed mode HPLC. In addition, LPTX and C-PTX showed different ion fragmentation patterns on MS/MS. These results suggest that LPTX and the palytoxins are structural isomers, containing at least one difference which gives rise to fluorescence in LPTX.

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PubMed1984

Characteristics of palytoxin-induced depolarization in squid axons.

The effects of palytoxin on squid axon membranes have been studied by means of internal perfusion and voltage clamp techniques. When applied externally at a concentration ranging from 1 X 10(-8) to 1 X 10(-6) M, palytoxin caused a large depolarization of the membrane that was reversed slowly after washing with toxin-free solution. The toxin-induced depolarization disappeared quickly upon decreasing the external sodium concentration from 445 to 1 mM and the membrane was hyperpolarized beyond the original level. Palytoxin did not cause depolarization if both external and internal solutions were devoid of sodium. The toxin-induced depolarization was only reversed partially by external application of 1 X 10(-6) M tetrodotoxin. Palytoxin had no effect on the resting potential when perfused internally. These results indicate that palytoxin acts from outside of the nerve membrane to increase sodium permeability, thereby causing a depolarization. The palytoxin-poisoned membrane was also permeable to other cations with a permeability ratio of Na/Li/Cs/NH4 = 1:0.62:0.75:1.45. Under voltage clamp conditions, palytoxin shifted the voltage dependence of peak sodium current and steady-state potassium current in the direction of hyperpolarization and reduced markedly the maximum amplitude of peak sodium current. However, the kinetics of sodium current underwent little or no change except a shift of voltage dependence toward hyperpolarization. Leakage current increased markedly after application of palytoxin. In view of these observations and data from the literature, it was suggested that palytoxin creates a new channel in the membrane, thereby causing an increase in cation permeability, depolarization, and other effects such as muscle contraction.

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PubMedDate not supplied

Cytotoxic actions of palytoxin on aortic smooth muscle cells in culture.

Palytoxin (PTX), isolated from a zoanthid of the genus Palythoa, is the most potent marine toxin known. Intoxication by PTX leads to vasoconstriction, hemorrhage, ataxia, muscle weakness, ventricular fibrillation, pulmonary hypertension, ischemia and death. In this study, clonal A7r5 rat aortic smooth muscle cells were used to study the mechanism of PTX-mediated cytotoxicity. A7r5 cells exposed to PTX for > or = 15 min exhibited surface granularities, vacuoles and rounding. These alterations culminated in a loss of viability as indicated by marked increases in the release of lactate dehydrogenase. Electrophysiological recording from A7r5 cells disclosed a profound membrane depolarization and an increase in conductance to Na+ and K+. PTX-mediated cytotoxicity could not be reversed by washout or by the addition of 10 microM verapamil but was antagonized by 100 microM ouabain or by removal of extracellular Na+ or Ca2+. In light of the involvement of vascular smooth muscle in PTX poisoning, A7r5 cells could serve as a useful model to test specific drugs for treatment of PTX intoxication.

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PubMed1989

Structure-activity studies of the nonphorbol tumor promoter palytoxin in Swiss 3T3 cells.

Derivatives of palytoxin have been prepared which are modified on either the hydroxyl terminus or the amino terminus of the molecule. Previously we have shown that palytoxin, a non-12-O-tetradecanoylphorbol-13-acetate-type tumor promoter, can inhibit epidermal growth factor binding in Swiss 3T3 cells through a pathway which is sodium dependent but not calcium or protein kinase C dependent. We used the epidermal growth factor receptor system to determine whether the specific chemical modifications of palytoxin present in these derivatives alter the cellular mechanism of action of the toxin. The dose response and ion dependence of palytoxin, the hydroxyl terminus derivative palytoxin-COOH, and the amino terminus derivatives N-acetylpalytoxin and N-(p-bromobenzoyl)palytoxin were compared with respect to inhibition of epidermal growth factor binding. The potency of palytoxin-COOH was similar to that of palytoxin. By contrast, N-acetylpalytoxin and N-(p-bromobenzoyl)palytoxin were approximately 1/100 as potent as palytoxin in this assay. All three derivatives were at least 100-fold less toxic than palytoxin. Like palytoxin, the activities of palytoxin-COOH, N-acetylpalytoxin and N-(p-bromobenzoyl)palytoxin were dependent upon the presence of extracellular sodium. However, there was a significant difference in the dependence of the derivatives on extracellular calcium. Our results suggest that the hydroxyl terminus is important for determining the calcium dependence of the molecule and the amino terminus is important for determining the biological potency of palytoxin. We conclude that modification of the hydroxyl terminus region is an effective means of reducing the toxicity of palytoxin while retaining the biological effects.

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PubMed1997

Palytoxin-induced single-channel currents from the sodium pump synthesized by in vitro expression.

Palytoxin, the most potent animal toxin, is proposed to convert Na+/K(+)-ATPase into a cation-selective ion channel. Because of the ubiquity of pumps and channels in the living tissues used to study its mechanism of action, it is difficult to rule out that another site may be involved. In order to show that palytoxin selectively acts on Na+/K(+)-ATPase, two entirely in vitro methods were employed: (1) a cell-free expression system to synthesize the rat alpha 3 and beta 1 subunit proteins, and (2) single-channel recording of the synthetic Na+/K(+)-ATPase reconstituted in a planar lipid bilayer. Upon addition of palytoxin, single-channel currents were induced which had a conductance of 10 pS, in agreement with previous studies. In control experiments, when the cDNAs for Na+/K(+)-ATPase subunits were omitted, no single-channel currents were induced with palytoxin. Thus, the results show unambiguously that the Na+/ K(+)-ATPase is the site of action for palytoxin. Because palytoxin turns the Na+/K(+)-ATPase into a channel which can be detected by the exquisitely sensitive single-channel recording technique, the present results are the first to demonstrate the activity of in vitro synthesized Na+/K(+)-ATPase.

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PubMed1995

Palytoxin. Recent electrophysiological and pharmacological evidence for several mechanisms of action.

1. Palytoxin is one of the most potent toxins known so far. It acts as an haemolysin and alters the functioning of excitable cells. 2. A primary action of palytoxin in excitable cells is to induce the activity of a small conductance (9-25 pS), non-selective cationic channel which then triggers secondary activations of voltage dependent Ca2+ channels and of Na+/Ca2+ exchange. This results in neurotransmitter release by nerve terminals and contractions of striated and smooth muscle cells. 3. Palytoxin induced channels are blocked by amiloride derivatives such as 3,4 dichlorobenzamil. They are also blocked by ouabain but at concentrations higher than those required to inhibit the (Na+,K+)ATPase. 4. A second and independent action of palytoxin is to open a membrane conductive pathway for H+ that drives H+ inside the cells and secondarily activates Na+/H+ exchange activity. 5. A third action of PTX in chick cardiomyocytes is to raise [Ca2+]i in a manner independent of its depolarizing action or of its action on intracellular pH. 6. It is suggested that PTX probably has more than one site of action in excitable cells and that it may act as an agonist for a family of low conductance channels that conduct Na+/K+, H+ and Ca2+ions.

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PubMed1999

Characterization of a palytoxin-induced non-selective cation channel in mouse megakaryocytes.

We used the whole-cell clamp and fura-2 techniques to study the membrane current and intracellular Ca2+ concentration ([Ca2+]i) changes of mouse megakaryocytes in response to palytoxin (PTX), a highly potent marine toxin. At a holding potential of -60 mV, PTX induced a sustained inward current in a dose-dependent manner. The reversal potentials measured in the presence of various extracellular major cations indicated that the PTX-induced channel had a non-selective permeability to alkali metal ions. Although elimination of intracellular Ca2+ had no effect on the PTX-induced current, removal of external Ca2+ inhibited the current activation. During the sustained phase of the PTX-induced current, treatment with ADP activated an additional current. Pretreatment with ouabain, an inhibitor of Na+-K+-ATPase, suppressed the PTX-induced current. During the stable phase of the PTX-induced current, challenge with NiCl2 (5 mM) or 2,4-dichlorobenzamil (DCB, 25 microM), a non-selective cation channel blocker, partially reversed the current. Simultaneous measurement of the membrane current and [Ca2+]i showed that PTX induced the current response without increasing the [Ca2+]i. Taken together, these results indicate that PTX induces a non-selective cation channel in mouse megakaryocytes. This channel is distinct from the ADP-operated channel and is sensitive to ouabain, NiCl2 and DCB.

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