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PubMed1994

Glucocorticoids do not affect intracellular calcium transients in corticotrophs: evidence supporting an effect distal to calcium influx.

The influx of extracellular calcium is a critical step involved in the stimulated release of adrenocorticotropin (ACTH) from pituitary corticotrophs. It has been proposed that the mechanism of early glucocorticoid feedback is mediated through inhibition of stimulus-evoked calcium transients. We tested this hypothesis using corticotrophic mouse pituitary AtT-20 cells by coevaluating secretory dynamics and cytosolic calcium transients. In static monolayer culture and in a dynamic microperifusion system, dexamethasone (DEX, 100 nM, 2 h) significantly inhibited ACTH secretion stimulated by corticotropin-releasing hormone (CRH, 100 nM). When ACTH was stimulated by KCl (56 mM) depolarization or the voltage-dependent calcium channel agonist, maitotoxin (MTX, 1 ng/ml), DEX did not inhibit secretion. In contrast, CRH-, KCl-, and MTX-stimulated ACTH secretion were significantly inhibited in static monolayer culture when cells were pretreated with the voltage-dependent calcium channel blocker, nifedipine (NIF, 1 microM, 15 min), confirming the requirement for the influx of extracellular calcium. Intracellular calcium was measured under similar culture conditions in populations of cells grown on coverslips, utilizing the fluorescent calcium indicator, fura-2. DEX had no effect on basal, spike, or plateau calcium levels in response to CRH, KCl or MTX stimulation. For example, CRH stimulation resulted in an increase in intracellular calcium from a basal concentration of 90 +/- 3.1 nM (mean +/- SE) to a plateau of 222 +/- 8.7 nM, whereas the plateau after DEX was 225 +/- 4.1 nM. In contrast, NIF significantly lowered the stimulated calcium response to each secretagogue (spike and plateau). These results do not support the hypothesis that glucocorticoids suppress stimulated secretion of ACTH from corticotrophs through an effect on intracellular calcium transients. Instead, the data suggest that early glucocorticoid negative feedback occurs at a step(s) distal to the influx of extracellular calcium.

Adrenocorticotropic Hormone↗
PubMed1987

Mechanisms subserving hormone action in the ovary: role of calcium ions as assessed by steady state calcium exchange in cultured swine granulosa cells.

We have appraised the properties of steady state calcium exchange in cultured swine granulosa cells prelabeled to isotopic equilibrium with 45Ca2+. Subsequent steady state efflux parameters were assessed by nonlinear least-squares curve-fitting to a two-compartment model. The resultant mean rate constants were 0.27 +/- 0.07 min-1 and 0.030 +/- 0.0015 min-1, which correspond to respective half-lives of calcium exchange of 2.6 +/- 0.67 min and 23 +/- 1.1 min (means +/- SD, n = 18 experiments). The estimated sizes of the rapidly and slowly exchangeable calcium compartments in ovarian cells were 1.8 +/- 0.51 and 4.47 +/- 0.15 mumol calcium/mg protein, respectively. Equilibrium exchange of calcium was temperature dependent, and accelerated markedly by putative stimulators of calcium influx, such as maitotoxin, A23187, and BAY K 8644. Conversely, presumptive inhibitors of the calcium-magnesium dependent ATPase, such as trifluoperazine and orthovanadate, significantly diminished the size of the slowly exchangeable pool and its corresponding rate constant. A similar profound reduction in the rate of slow calcium exchange was induced by a phorbol ester and by an inhibitor of intracellular calcium mobilization, dantrolene. Physiological effector hormones also altered equilibrium calcium exchange in swine granulosa cells. Thus, FSH and prostaglandin E2 increased the rapid and slowly exchanging rate constants by factors of approximately 2.2 and 1.6, whereas prostaglandin F2 alpha increased the sizes of the slowly and rapidly exchangeable calcium compartments. In summary, the present work delineates properties of physiological steady state calcium exchange in swine granulosa cells. Physiological effector hormones, such as FSH, prostaglandin E2, and prostaglandin F2 alpha, have distinct effects on steady state calcium exchange in ovarian cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1975

Palytoxin: effects on contractility and 45Ca2+ uptake in isolated ventricle strips.

Palytoxin (PTX) inhibited phasic tension production and initiated tonic contracture in isolated paced ventricle strips at concentrations greater than 10(-10) M. PTX-induced contracture was associated with increased 45Ca2+ uptake. PTX-induced additional 45Ca2+ uptake was completely blocked by 2 mM La3+. All observed PTX effects were enhanced by elevation of [Ca2+] o from 1.9 to 6 mM and this threefold increase in [Ca2+] o resulted in a threefold increase in isotope-determined Ca2+ uptake in presence of 10(-8) M PTX. It is concluded that the observed effects of PTX could be mediated by an increase in calcium permeability of myocardial cells.

Acrylamides↗
PubMed2002

Ionic mechanisms involved in the nodal swelling of myelinated axons caused by marine toxins.

This review describes the ionic mechanisms involved in the nodal swelling of frog myelinated axons caused by specific marine neurotoxins (ciguatoxins, brevetoxins, Conus consors toxin and equinatoxin-II), analysed using confocal laser scanning microscopy. We have focussed on toxins that either target neuronal voltage-dependent Na+ channels, or that form cation-selective pores and indirectly affect the functioning of the Na(+)-Ca(++)exchanger.

Animals↗
PubMed1992

Maitotoxin effects are blocked by SK&F 96365, an inhibitor of receptor-mediated calcium entry.

The dinoflagellate toxin maitotoxin (MTX) elicited a sustained increase of [Ca2+]i in C6 glioma cells. This response was inhibited by SK&F 96365, a blocker of receptor-mediated calcium entry. In C6 cells, endothelin-1 elicited a rapid but transient increase in [Ca2+]i, followed by a smaller sustained increase. SK&F 96365 inhibited the sustained increase in [Ca2+]i. In both C6 glioma cells and RIN insulinoma cells, MTX elicited a marked influx of 45Ca2+. SK&F 96365 inhibited MTX-induced 45Ca2+ influx by 95% at 30 microM. The L-type calcium channel blocker nifedipine, even at 10 microM, inhibited MTX-induced calcium uptake by only 20% in RIN cells and by only 10% in C6 cells. MTX elicited calcium-dependent phosphoinositide breakdown in both C6 and RIN cells. In both cell lines, the MTX-induced phosphoinositide breakdown was inhibited by 90% by SK&F 96365 at 30 microM. Endothelin-1 and carbamylcholine elicited phosphoinositide breakdown in C6 cells and RIN cells, respectively. The stimulations were unaffected by the presence of SK&F 96365 up to 100 microM. In RIN insulinoma cells, MTX elicited calcium-dependent release of insulin. SK&F 96365 at 30 microM inhibited MTX-induced insulin release by 75%, whereas nifedipine, even at 30 microM, inhibited release by only 10%. The blockade of MTX-induced responses by SK&F 96365 indicates that MTX increases intracellular calcium by interacting directly with a calcium-entry system that is similar, in its sensitivity to SK&F 96365, to the calcium-entry system activated by receptors that elicit phosphoinositide breakdown. Activation of phospholipase C and hormone release by MTX also are blocked by SK&F 96365 and, thus, may be secondary to the activation of such a calcium-entry system.

Calcium↗
PubMed1986

Cardiotoxic effects of maitotoxin, a principal toxin of seafood poisoning, on guinea pig and rat cardiac muscle.

Maitotoxin (MTX), a principal toxin of seafood poisoning, produced powerful cardiotoxic effects on guinea pig isolated left atria at concentrations of 5 X 10(-9) to 3 X 10(-8) g/ml. The MTX-induced increase in resting tension of atria was abolished by Co++, D600 or Ca++-free solution. The tissue Ca content and 45Ca uptake of guinea pig atria were increased by MTX (5 X 10(-9) to 3 X 10(-8) g/ml), and these increases were inhibited markedly by Co++. In isolated rat cardiac myocytes, irreversible contracture was produced by MTX (10(-8) g/ml), and this effect of MTX was suppressed by verapamil or Ca++-free solution. The intracellular free Ca++ concentration of isolated rat myocytes was increased greatly by MTX (10(-9) to 3 X 10(-8) g/ml). Furthermore, the myocardial cells sampled from guinea pig left atria were characterized ultrastructurally by severely overcontracted sarcomeres, swollen mitochondria, peripheral aggregation of nuclear chromatin and loss of granular glycogen, and these morphological changes were abolished by omitting Ca++ from the medium. These results suggest that MTX increases the Ca++ influx through the cardiac muscle membrane to create the Ca-overloaded state and thus caused the cardiotoxic effects.

Animals↗
PubMed1994

Depletion of intracellular Ca2+ stores activates a maitotoxin-sensitive nonselective cationic current in beta-cells.

Glucose stimulation of beta-cell insulin secretion is initiated by membrane depolarization coupled with an elevation in intracellular Ca2+ concentration ([Ca2+]i). Both depolarization-dependent Ca2+ entry and intracellular Ca2+ store release contribute to the sugar-induced rise in [Ca2+]i. Here we show that maneuvers depleting intracellular Ca2+ stores induce membrane depolarization and a sustained nitrendipine-sensitive Ca2+ influx, whereas interventions promoting Ca2+ store refilling produce a hyperpolarization and inhibit Ca2+ influx. Both intracellular Ca2+ store depletion and maitotoxin activated a depolarizing nonselective cation current carried principally by Na+ in the physiological range of membrane potentials. The activation of such a current may form the paradigm by which excitable cells refill depleted intracellular Ca2+ stores by depolarization-driven opening of voltage-activated Ca2+ channels.

Animals↗
PubMed1996

Brevetoxin-3 (PbTx-3) on mouse liver slices: a histological study.

Brevetoxin-3 (PbTx-3) is a marine toxin produced by the dinoflagellate Ptychodiscus brevis. Its effects on excitable tissues have been the main subject of studies, but little is known about how it affects non-excitable tissues. To study possible non-neural effects of PbTx-3 (78nM), its effects on hepatic cell structure in vitro were evaluated. PbTx-3 caused hypertrophy and increased vacuolation of hepatocytes, and an increase in basophilia in the perivenous area of the lobules. Ultrastructurally, it was evident that the vacuolation was related to swelling of the endoplasmic reticulum, changes that probably account for the increased basophilic reaction of the cells. The swelling in smooth endoplasmic reticulum, degranulation of rough endoplasmic reticulum, the deformities and lytic cristae in the mitochondria, and the presence of active lysosomes are evidence of the PbTx-3 effects upon liver cells. These responses are probably caused by the liver's detoxification role on the PbTx-3.

Animals↗
PubMed2005

Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation.

Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution. Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available. Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities. In fact, it could be argued that the characterization of natural products has become a routine task, one which no longer even requires a reaction flask! This Review makes the case that imaginative detective work and chemical synthesis still have important roles to play in the process of solving nature's most intriguing molecular puzzles.

Biological Products↗
PubMed2003

Elucidation of the fragmentation pathways of azaspiracids, using electrospray ionisation, hydrogen/deuterium exchange, and multiple-stage mass spectrometry.

Collision-induced dissociation (CID) mass spectra were generated for azaspiracids using electrospray ionisation (ESI), and hydrogen/deuterium (H/D) exchange was used to ascertain the number and type of replaceable hydrogens in the three predominant azaspiracid toxins. H/D exchange was conveniently achieved using deuterated solvents for liquid chromatography (LC). Using ion-trap mass spectrometry, multiple-stage CID experiments (MS(n)) on the protonated and fully exchanged ions were performed to decipher characteristic fragmentation pathways. The precursor and product ions from azaspiracids lost up to five water molecules from different regions during MS(n) experiments and it was possible to distinguish between the water losses from different molecular regions. These studies confirmed that the first water-loss ion in the spectra of azaspiracids resulted from dehydration at the vicinal diol at C20-C21. Five MS dissociation pathways were identified that resulted from fragmentation of the carbon skeleton of azaspiracids producing nitrogen-containing ions. Two pathways, involving cleavage of the E-ring and C27-C28, gave ions that were found in all azaspiracids. Three pathways, A-ring, C-ring and C19-C20 cleavages, were useful for distinguishing between azaspiracid analogues. The same product ions from backbone fragmentation were also observed using hybrid quadrupole time-of-flight mass spectrometry (QqTOFMS). The fragmentation of the A-ring was the most facile and was exploited in the development of LC/MS(n) methods for the analysis of azaspiracids.

Animals↗
PubMed2002

Studies on azaspiracid biotoxins. II. Mass spectral behavior and structural elucidation of azaspiracid analogs.

In this report, the mass spectral analysis of azaspiracid biotoxins is described. Specifically, the collision-induced dissociation (CID) behavior and differences between CID spectra obtained on a triple-quadrupole, a quadrupole time-of-flight, and an ion-trap mass spectrometer are addressed here. The CID spectra obtained on the triple-quadrupole mass spectrometer allowed the classification of the major product ions of the five investigated compounds (AZA 1-5) into five distinct fragment ion groups, according to the backbone cleavage positions. Although the identification of unknown azaspiracids was difficult based on CID alone, the spectra provided sufficient structural information to allow confirmation of known azaspiracids in marine samples. Furthermore, we were able to detect two new azaspiracid analogs (AZA 1b and 6) in our samples and provide a preliminary structural analysis. The proposed dissociation pathways under tandem mass spectrometry (MS/MS) conditions were confirmed by a comparison with accurate mass data from electrospray quadrupole time-of-flight MS/MS experiments. Regular sequential MS(n) analysis on an ion-trap mass spectrometer was more restricted in comparison to the triple-quadrupole mass spectrometer, because the azaspiracids underwent multiple [M + H - nH(2)O](+) (n = 1-6) losses from the precursor ion under CID. Thus, the structural information obtained from MS(n) experiments was somewhat limited. To overcome this limitation, we developed a wide-range excitation technique using a 180-u window that provided results comparable to the triple-quadrupole instrument. To demonstrate the potential of the method, we applied it to the analysis of degraded azaspiracids from mussel tissue extracts.

Animals↗
PubMed2002

Structural confirmation of ostreocin-D by application of negative-ion fast-atom bombardment collision-induced dissociation tandem mass spectrometric methods.

Negative-ion fast-atom bombardment collision-induced dissociation tandem mass spectrometric (FAB-CID-MS/MS) methodology was successfully applied to verify the highly complex structure of ostreocin-D (MW 2633), a new palytoxin analog isolated from the marine dinoflagellate Ostreopsis siamensis and proposed to be 42-hydroxy-3,26-didemethyl-19,44-dideoxypalytoxin based on NMR data. The charge-remote fragmentations were facilitated by a negative charge introduced to a terminal amino group or to a hydroxyl group at the other terminus by a reaction with 2-sulfobenzoic acid cyclic anhydride. Product ions generated from the [M - H](-) ions provided information on the structural details of ostreocin-D. Comparisons between the spectral data for ostreocin-D and palytoxin also provided a rational basis for the assignments of product ions.

Acrylamides↗
PubMed1992

An approach to computer-aided inhibitor design: application to cathepsin L.

We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80,000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the 'red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 microM and 0.6 microM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.

Binding Sites↗
PubMed1994

Characterization of [3H]brevetoxin binding to voltage-dependent sodium channels in adrenal medullary cells.

We have previously reported that in bovine adrenal chromaffin cells Ptychodiscus brevis toxin-3 (PbTx-3) does not alter the veratridine-induced 22Na influx when given alone, but increases the influx of 22Na when co-applied with either alpha- or beta-scorpion venom (Wada et al. 1992). In the present study, we characterized [3H]PbTx-3 binding in bovine adrenal chromaffin cells. [3H]PbTx-3 binding was saturable, reversible and of high-affinity with an equilibrium dissociation constant (Kd) of 32.0 +/- 4.9 nmol/l and a maximum binding capacity (Bmax) of 6.2 +/- 1.2 pmol/4 x 10(6) cells (4.5 +/- 0.9 pmol/mg cell protein). A Hill plot revealed the lack of cooperative interaction among the binding sites. Unlabelled PbTx-3 inhibited [3H]PbTx-3 binding with an IC50 of 31 nmol/l. However, tetrodotoxin, veratridine, alpha- and beta-scorpion venom, or veratridine in combination with either alpha- or beta-scorpion venom did not alter [3H]PbTx-3 binding. All these results suggest that PbTx-3 binds to a site (site 5) distinct from the previously known four toxin binding sites, which does not gate voltage-dependent Na channels by itself, but is specifically involved in the allosteric modulation of Na channels in adrenal medullary cells.

Adrenal Medulla↗
PubMed1988

Differential effects of maitotoxin on ATP secretion and on phosphoinositide breakdown in rat pheochromocytoma cells.

Maitotoxin (MTX) induced exocytotic secretion of ATP from PC12 rat pheochromocytoma cells. The threshold for stimulation of secretion was at concentrations of about 2 ng/ml of MTX. Maximal release occurred at 40 ng/ml. MTX-induced ATP release required the presence of calcium in the extracellular medium and could be inhibited by nifedipine, a specific blocker of voltage-dependent calcium channels. In addition to the effects on ATP secretion from PC12 cells, MTX stimulated the breakdown of phosphoinositides, as measured by the accumulation of [3H]inositol phosphates. Maximal stimulation of phosphoinositide breakdown was reached at only 0.5-1.0 ng/ml MTX. MTX at concentrations required to evoke ATP release (greater than 2 ng/ml) had lesser or no effect on phosphoinositide breakdown. Although stimulation of phosphoinositide breakdown by MTX was dependent on extracellular calcium, it was insensitive to the calcium channel blockers nifedipine, D-600 and cobalt ions. The different concentration range required to elicit these responses and the varying sensitivity to calcium channel blockers indicate that MTX-evoked secretion and MTX-stimulated phosphoinositide breakdown are independent phenomena in PC12 cells.

Adenosine Triphosphate↗
PubMed1990

Maitotoxin-induced myocardial cell injury: calcium accumulation followed by ATP depletion precedes cell death.

Maitotoxin, the most potent marine toxin, is known to increase the uptake and the accumulation of Ca2+ into cells, and was used in the present study to investigate the mechanisms of myocardial cell damage induced by Ca2+ overload. In cultured cardiomyocytes, isolated from 2-day-old rats, maitotoxin affected cell viability, as indicated by the leakage of the cytosolic enzyme lactate dehydrogenase (LDH) and of radiolabeled adenine nucleotides into the extracellular medium. Maitotoxin-induced leakage of LDH steadily increased between 30 min and 24 hr, and was preceded by a marked depletion of intracellular ATP. Addition of maitotoxin resulted in a rapid influx of extracellular Ca2+, as detected by preincubating the cells in the presence of 45Ca; this effect evolved in a few minutes, thus preceding the signs of cell death. Cytosolic levels of free Ca2+ ([Ca2+]i) were monitored by loading freshly isolated, suspended cardiomyocytes with the intracellular fluorescent probe fura-2; in these cells, maitotoxin induced a dose-dependent increase in [Ca2+]i, with a lag phase of less than a minute. All these effects of maitotoxin were inhibited by reducing Ca2+ concentration in the culture medium or by incubating the cells with the calcium-channel blocking drug verapamil. It is thus demonstrated that maitotoxin-induced cardiotoxicity is secondary to an inordinate influx of Ca2+ into the cells. It is also suggested that, in those conditions that lead to an inordinate accumulation of Ca2+ into myocardial cells, the unmatched demands of energy and the depletion of ATP play a primary role in the irreversible stage of cell damage.

Adenosine Triphosphate↗