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At least 217 records · Page 12Linked to original sources
PubMed1987

Maitotoxin-induced membrane current in neuroblastoma cells.

Maitotoxin (MTX) is a potent marine toxin isolated from the toxic dinoflagellate, Gambierdiscus toxicus. We have examined the possibility of MTX activating calcium channels using cultured neuroblastoma cells (N1E-115). MTX (10 ng/ml) produced a depolarization of the membrane, which was prevented by the removal of Ca2+ from the external medium. Under voltage clamp conditions, membrane currents were recorded with 50 mM Ba2+ as a charge carrier through calcium channels. After application of MTX (1 ng/ml), an inward current necessary to hold the membrane at -90 mV increased progressively. This was followed by a gradual decrease of the transient inward Ba2+ current through type I calcium channels recorded at -30 mV which was eventually abolished. A similar tendency was observed in the long-lasting inward Ba2+ current through type II calcium channels, which was recorded at +10 mV. The MTX action was antagonized by calcium channel blockers such as verapamil (100 microM) and La3+ (1 mM). A high concentration of verapamil (500 microM) blocked both types of calcium channels persistently. After washout of verapamil but while the calcium channels were still blocked, MTX (1 ng/ml) induced a steady-state current. The MTX-induced current showed an inward-rectifying property with a reversal potential of approximately -30 mV. The results suggest that the MTX-induced current does not flow through calcium channels. Thus, MTX may create a pore in the membrane with pharmacological properties similar to those of calcium channels.

Animals↗
PubMed1989

Maitotoxin, a potent, general activator of phosphoinositide breakdown.

Maitotoxin (MTX), a potent marine toxin, elicits a calcium-dependent activation of cells that can be inhibited by calcium channel blockers like nifedipine. MTX also stimulates phosphoinositide breakdown in smooth muscle cells, NCB-20 cells and PC12 cells through a nifedipine-insensitive mechanism. We now report that MTX stimulates phosphoinositide breakdown in a wide variety of cells, and appears to represent the first general activator of this second messenger-generating system. MTX-induced stimulation of phosphoinositide breakdown is dependent in every cell line on the presence of extracellular calcium. In differentiated HL60 cells, in which a chemotactic peptide (fMLP) activates phosphoinositide breakdown via a pertussis toxin-sensitive mechanism, MTX-induced stimulation is not affected by pertussis toxin treatment. A phorbol ester has no effect on the response to MTX. Thus, MTX stimulates phosphoinositide breakdown through a calcium-dependent mechanism that at least in three cell lines (PC12, NCB20 and HL60) is not mediated by a pathway that involves a pertussis toxin-sensitive guanine nucleotide-binding protein.

Animals↗
PubMed1994

Effect of ganglioside GM1 on arachidonic acid release in bovine aortic endothelial cells.

A role for the ganglioside GM1 in arachidonic acid release in bovine aortic endothelial cells (BAEC) was investigated. [3H]Arachidonic acid-labeled BAEC were preincubated with GM1 and incubated with one of four different stimulators. GM1 inhibited arachidonic acid release when stimulated with maitotoxin or melittin but not with ionomycin or thapsigargin. A 10 microM GM1 concentration achieved a 50% and 100% inhibition of the maitotoxin and melittin responses, respectively. The selective inhibition displayed by GM1 on the maitotoxin and melittin responses was not due to its ability to bind calcium since all four drugs, maitotoxin, melittin, ionomycin, and thapsigargin, required extracellular calcium. The effect of GM1 was not specific to arachidonic acid release. GM1 at 50 microM inhibited phosphatidylinositol polyphosphate (PIP) hydrolysis mediated by melittin, but did not affect hydrolysis mediated by ionomycin. Moreover, the activity of GM1 was not restricted to phospholipid metabolism since it also inhibited calcium influx that was stimulated by maitotoxin or melittin but not by ionomycin. We conclude that GM1 is not a specific inhibitor of phospholipases in bovine aortic endothelial cells, but rather its activity is dependent on the type of stimulant used to activate the cell.

Animals↗
PubMed1988

Brevetoxin binding: molecular pharmacology versus immunoassay.

Brevetoxin PbTx-3 isolated from Florida's red tide dinoflagellate Ptychodiscus brevis has been produced recently in tritiated form by reductive tritiation of brevetoxin PbTx-2. Tritiated PbTx-3 has been used as a specific probe in competitive radioimmunoassays developed to detect brevetoxins in food sources, and this probe has also been utilized to characterize the brevetoxin binding component in rat brain synaptosomes. Brevetoxins PbTx-2 and PbTx-3, possessing the same structural backbone (type-1) as the tritiated probe, and PbTx-1 and PbTx-7, possessing a second structural backbone (type-2), have been compared quantitatively in their individual abilities to competitively displace tritiated PbTx-3 from its specific binding site in each assay. Type-1 toxins displaced labeled probe with ED50 values of 20-22 nM and 12-17 nM in radioimmunoassay and synaptosomes, respectively. Type-2 toxins displaced labeled probe with ED50 values of 92-93 nM and 3.5-4.1 nM in RIA and synaptosomes, respectively. Synaptosome assays reflect potency of each toxin examined, while radioimmunoassay reflects structural similarities to the immunizing toxin PbTx-3.

Animals↗
PubMed1990

Toxicity of Australian and French polynesian strains of Gambierdiscus toxicus (Dinophyceae) grown in culture: characterization of a new type of maitotoxin.

Gambierdiscus toxicus strains isolated from Australia and French Polynesia were grown in modified f2 and f10 nutrient media and the cells extracted for ciguatoxin and maitotoxin. The high nutrient enrichment of f2 media induced aberrant cell morphology in both strains whereas the majority of cells grown in f10 media had the typical lenticular shape of wild G. toxicus cells. The Australian strain grew faster and produced greater cell densities than the French Polynesian strain. Different chromatographic types of maitotoxin were extracted from the two G. toxicus strains and purified to homogeneity using reverse-phase high-performance liquid chromatography. The toxins elicited similar bioassay signs in mice, but produced different death-time vs dose relationships. The maitotoxin extracted from the Australian strain eluted later on both straight-phase and reverse-phase chromatographic columns than did the maitotoxin extracted from the French Polynesian strain. The maitotoxin extracted from the French Polynesian strain was chromatographically identical to reference maitotoxin. For each strain no differences were found between maitotoxins extracted from cells grown in f2 or f10 media. Only one toxin was produced by each strain of G. toxicus. Ciguatoxin was not produced by either strain.

Animals↗
PubMed1991

In vitro penetration of tritium-labelled water (THO) and [3H]PbTx-3 (a red tide toxin) through monkey buccal mucosa and skin.

The permeability coefficients (Kp) for tritium-labelled water (THO) were determined in human and monkey skin, and monkey buccal mucosa. Kp of human skin (0.47 x 10(-3) cm/h) correlated favorably with previous reports. Kp of hydrated monkey skin for THO (0.77 x 10(-3) cm/h) was not significantly different (P greater than 0.05) from Kp of hydrated human skin (0.88 x 10(-3) cm/h). Kp of monkey buccal mucosa for THO (6.15 x 10(-3) cm/h) was significantly greater than that for monkey skin. Penetration and disposition of [3H]PbTx-3 into layers of monkey buccal mucosa and skin was determined. [3H]PbTx-3 (5-7 microCi) dissolved in 2 ml of water was applied to epithelial/epidermal surface (2.8 cm2) at zero time. The relative percent dose recovered from the upper layers of buccal mucosa (epithelium) and skin (epidermis) varied, but at each time interval was less than 2.5% of the dose. At most of the time intervals (2-24 h), a larger percent of the dose was recovered from the inner layer of the buccal mucosa (lamina propria) than from the inner layer of skin (dermis). After 24 h, as much as 34 or 13% of the dose was recovered from lamina propria or dermis, respectively. At each time interval studied, less than 2% of dose of [3H]PbTx-3 penetrated into the receptor fluid which bathed the inner surfaces of the lamina propria or dermis. The results of this study demonstrate that monkey buccal mucosa is more permeable than skin to THO and PbTx-3.

Administration, Topical↗
PubMed1996

Regeneration and luminescence of aequorin in Chinese hamster ovary cells transformed with cDNA for apoaequorin.

Aequorin, a photoprotein which is regenerated from apoaequorin by incubation with coelenterazine, emits light when it binds Ca2+. The aim of this study was to determine if apoaequorin could be used in adherent mammalian cells for measuring cytosolic Ca2+, and imaging Ca2+, at the single cell level. Chinese hamster ovary (CHO-K1) cells were stably transformed with apoaequorin cDNA and expressed apoaequorin while attached to the culture dishes. Maximal luminescence intensity was obtained when 0.5 x 10(6) cells/ml were grown and incubated with 2.5 microM coelenterazine for 4 hr at 20 degrees C. Ca2+ mobilizing agents (ionomycin and maitotoxin) induced luminescence in CHO-K1 transformed cells. However, imaging of light emission from single cells proved to be unsuccessful. Ca2+ could be readily measured in the adherent CHO-K1 cells, but imaging was not possible at the single cell level.

Aequorin↗
PubMed2005

Tissue distribution, effects of cooking and parameters affecting the extraction of azaspiracids from mussels, Mytilus edulis, prior to analysis by liquid chromatography coupled to mass spectrometry.

This study used liquid chromatography coupled to mass spectrometry to identify some parameters important in the analysis of azaspiracids. The first aspect was the distribution of azaspiracids within mussels, in particular the content in the digestive gland as compared to the remaining tissues. In our study, azaspiracids accumulated in the digestive gland, similar to other lipophilic toxins. The ratio of toxin in the digestive gland compared to the whole mussel was on average circa 5, both for a bulk sample collected in Norway in 2004 and for 28 samples from Ireland collected over 3 years (2001-2003). These results may justify the practise to only analyse the digestive gland, a step considered necessary to achieve adequate detection limits for azaspiracids both in the mouse bioassay and other analytical techniques. Steaming of mussels as a sample pre-treatment was found to be another parameter affecting the result. Azaspiracids concentrated indirectly, i.e. through the loss of water or juice from the matrix. The cooked shellfish tissues had a concentration of azaspiracids 2-fold higher than the uncooked shellfish, both for whole flesh and for digestive gland tissue. This finding is of particular importance since it may affect the maximum guidance level at which shellfish may be allowed for human consumption. Finally, parameters affecting the extraction efficiency were studied, including the nature of the extraction solvent, the sample-to-solvent ratio and replicate extraction. The largest differences were observed between different solvents and between different sample-to-solvent ratios, while the effect of replicate extraction was minimal if large sample-to-solvent ratios were used. Duplicate extraction using 100% methanol was found to be the best combination of parameters.

Animals↗
PubMed2006

Identification of pectenotoxins in plankton, filter feeders, and isolated cells of a Dinophysis acuminata with an atypical toxin profile, from Chile.

A bloom of Dinophysis acuminata produced, in autumn of 2005, a closure of the scallop harvesting in Bahía Inglesa, in the Chilean III region. Isolated cells of this Dinophysis species were shown to contain 180 pg cell(-1) of pectenotoxin 2 but neither okadaic acid nor any of its analogs or derivatives (at least at a detectable level). Examination of plankton and filter-feeder samples covering an area of ca. 350 km, from the location where the toxicity was recorded to Bahía Tongoy, showed that the unique toxin profile found in the first bloom was widespread over that part of Chile and persisted for months. The analysis were carried out by HPLC-ESI-MS using positive ionization mode, with a detection limit below 2 ng of OA mL(-1) of methanolic extract. This is the first report of the presence of pectenotoxins in the plankton of the Pacific coast of America and in the studied filter feeders. This is also the first report of a Dinophysis species containing pectenotoxins and not any toxin of the okadaic acid group.

Animals↗
PubMed2003

Allosteric interactions among pyrethroid, brevetoxin, and scorpion toxin receptors on insect sodium channels raise an alternative approach for insect control.

Intensive pyrethroid use in insect control has led to resistance buildup among various pests. One alternative to battle this problem envisions the combined use of synergistically acting insecticidal compounds. Pyrethroids, scorpion alpha- and beta-toxins, and brevetoxins bind to distinct receptor sites on voltage-gated sodium channels (NaChs) and modify their function. The binding affinity of scorpion alpha-toxins to locust, but not rat-brain NaChs, is allosterically increased by pyrethroids and by brevetoxin-1. Brevetoxin-1 also increases the binding of an excitatory beta-toxin to insect NaChs. These results reveal differences between insect and mammalian NaChs and may be exploited in new strategies of insect control.

Allosteric Regulation↗
PubMed2001

Maitotoxin-induced calcium entry in human lymphocytes: modulation by yessotoxin, Ca(2+) channel blockers and kinases.

We have studied the effect of the ciguatera-related toxin maitotoxin (MTX) on the cytosolic free calcium concentration ([Ca(2+)]i) of human peripheral blood lymphocytes loaded with the fluorescent probe Fura2 and the regulation of MTX action by different drugs known to interfere in cellular Ca(2+) signalling mechanisms and by the marine phycotoxin yessotoxin (YTX). MTX produced a concentration-dependent elevation of [Ca(2+)]i in a Ca(2+)-containing medium. This effect was stimulated by pretreatment with YTX 1 microM and NiCl(2) 15 microM. The voltage-independent Ca(2+) channel antagonist 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenyl]-1H-imidazole hydrochloride (SKF96365) blocked the MTX-induced [Ca(2+)]i elevation, while the L-type channel blocker nifedipine had no effect. Pretreatment with NiCl(2) or nifedipine did not modify YTX-induced potentiation of MTX effect, and SKF96365-induced inhibition was reduced in the presence of YTX, which suggest different pathways to act on [Ca(2+)]i. Preincubation with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89) or genistein (10 microM) also had no effect on the MTX-induced [Ca(2+)]i increment. In contrast, the PKC inhibitor bisindolilmaleimide I (GF109203X 1 microM) potentiated the MTX effect, whereas phosphatidylinositol (PI) 3-kinase inhibition with wortmannin (10 nM) reduced the MTX-elicited Ca(2+) entry. In summary, MTX produced Ca(2+) influx into human lymphocytes through a SKF96365-sensitive, nifedipine-insensitive pathway. The MTX-induced [Ca(2+)]i elevation was stimulated by the marine toxin YTX through a mechanism insensitive to SKF96365, nifedipine or NiCl(2). It was also stimulated by the divalent cation Ni(2+) and PKC inhibition and was partially inhibited by PI 3-kinase inhibition.

Calcium↗
PubMed2004

Effects of Azaspiracids 2 and 3 on intracellular cAMP, [Ca2+], and pH.

Azaspiracids (AZs) are a new group of phycotoxins discovered in the Ireland coast that includes the isolated analogues: AZ-1, AZ-2, AZ-3, AZ-4, and AZ-5 and the recently described AZ-6-11. Toxic episodes of AZs show gastrointestinal illness as in diarrhetic shellfish poisoning, but neurotoxic symptoms are also observed in a mouse bioassay. Despite their great importance in human health, so far, its mechanism of action is largely unknown. In this report, we present the first data of AZ-2 and AZ-3 effects on intracellular cyclic adenosine monophosphate (cAMP), intracellular calcium ([Ca(2+)](i)), and cytosolic pH levels (pH(i)) in freshly human lymphocytes. The variations of cAMP, calcium, and pH were determined by fluorescence digital imaging microscopy using recombinant fluorescein- and rhodamine-labeled protein kinase A, Fura2-AM, and 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester, respectively. Our experiments show that both analogues, AZ-2 and AZ-3, clearly increase cytosolic cAMP levels of human lymphocytes. In calcium studies, we found that only if cells are initially in a calcium-free medium, AZ-2 increases the intracellular calcium concentration with two components: Ca(2+) release from internal stores and Ca(2+) influx from extracellular medium. AZ-2 sensitive Ca(2+) stores seem to be different from the thapsigargin sensitive one. AZ-2-induced Ca(2+) influx is mediated through Ni(2+) and SKF96365 blockable channels, and it is additive with Tg-induced Ca(2+) influx. Surprisingly, AZ-3 does not empty intracellular stores but also increases cytosolic calcium levels. This AZ-3-induced Ca(2+) influx is mediated through Ni(2+) blockable channels, and it is not additive with Tg-induced Ca(2+) influx. In addition, AZ-3 slightly alkalinizes cytosol. In accordance with cAMP studies, we found that adenylyl cyclase (AC) modulation inhibits AZ-2- and AZ-3-evoked Ca(2+) increase and AZ-3-induced pH(i) rise. Thus, both analogues seem to involve an AC pathway, although its effects on [Ca(2+)](i) and pH(i) are quite different.

Calcium↗
PubMed1999

Solution reactivity of brevetoxins as monitored by electrospray ionization mass spectrometry and implications for detoxification.

The reactivities of brevetoxin compounds in acid and base and under oxidizing conditions were studied using electrospray ionization mass spectrometry (ESI-MS) to monitor reaction products. Brevetoxins are determined to be unstable in acidic and basic solutions. Under acidic conditions, brevetoxins containing an aldehyde functional group in the terminal "tail" side chain are easily converted to acetal structures, while "head" side lactone ring opening proceeds more slowly. Measurement of reaction rate constants indicates the following order of reactivity under acidic conditions: Btx-1 > Btx-2 > Btx-9. Under basic conditions, hydroxide ion attack at the head portion leads to lactone ring opening. Base hydrolysis (0.01 N NaOH in 50:50 methanol/water) goes to completion in 120 min for Btx-2 and Btx-9, but Btx-1 did not react to completion. Both acid and base hydrolyses can lead to reversible lactone ring opening, but base hydrolysis proceeds faster than acid hydrolysis under comparable conditions. Acid treatment is not an effective method for detoxifying brevetoxins. Base treatment can open the lactone ring (type B brevetoxins proceed faster than type A brevetoxins), leading to a product that is reportedly nontoxic, but the reaction is reversible. Brevetoxins are shown to be readily oxidized by permanganate in an irreversible and relatively fast reaction, likely through addition to double bonds followed by bond cleavage, suggesting that it is a viable method for detoxification.

Animals↗
PubMed2002

Reserpine: interactions with batrachotoxin and brevetoxin sites on voltage-dependent sodium channels.

Reserpine inhibited batrachotoxin-elicited sodium influx in guinea pig brain synaptoneurosomes with an IC50 of about 1 microM. In the presence of brevetoxin the IC50 increased to about 80 microM. Reserpine inhibited binding of batrachotoxinin-A [3H]benzoate ([3H]BTX-B) binding in a complex manner causing a partial inhibition from 0.001 to 0.08 microM, then a rebound stimulation from 0.1 to 0.8 microM, followed by complete inhibition by 80 microM. The stimulation was prevented by the presence of brevetoxin; reserpine then smoothly inhibited binding with an IC50 of about 1 microM. Reserpine at 1 microM slightly reduced the off-rate of [3H]BTX-B binding measured in the presence of veratridine, while at a concentration of 50 microM it enhanced the off-rate, presumably by an allosteric mechanism. Reserpine at 0.3-10 microM elicited a partial inhibition of the binding of [3H]brevetoxin-3. The local anesthetic dibucaine had effects similar to reserpine: It partially inhibited binding of [3H]brevetoxin. The presence of brevetoxin reduced the potency of dibucaine as an inhibitor of batrachotoxin-elicited sodium influx from an IC50 of about 2 microM to an IC50 of about 50 microM. The results suggest that reserpine binds at both a local anesthetic site to cause allosteric inhibition of batrachotoxin-binding and action, but that it also binds to another site causing, like brevetoxin, an enhancement of batrachotoxin-binding and action. Local anesthetics also may bind to the brevetoxin site.

Animals↗