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Biomedical subjects

H Schweitz

Publications and source records attributed to H Schweitz.

47 records · Page 3Linked to original sources
PubMed1977

Effects of neurotoxins (veratridine, sea anemone toxin, tetrodotoxin) on transmitter accumulation and release by nerve terminals in vitro.

Two of the tree toxic compounds used in this work, veratridine and the sea anemone toxin, provoke neurotransmitter release from synaptosomes; the third one, tetrodotoxin, prevents the action of both veratridine and the sea anemone toxin. The half-maximum effects of veratridine and sea anemone toxin actions on synaptosomes are K0.5 = 10 and 0.02 micronM, respectively. Although veratridine and the sea anemone toxin similarly provoke neurotransmitter release, they act on different receptor structures in the membrane. Tetrodotoxin antagonizes the effects of both veratridine and the sea anemone toxin. The half-maximum inhibitory concentration of tetrodotoxin is K0.5 = 4 nM for veratridine and 7.9 nM for ATXII. It is very similar to the dissociation constant measured from direct binding experiments with the radioactive toxin. The analysis of this antagonistic action offers an easy in vitro assay for tetrodotoxin interaction with its receptor.

Animals↗
PubMed1976

Molecular mechanism of cardiotoxin action on axonal membranes.

Cardiotoxin isolated from Naja mossambica mossambica selectively deactivates the sodium-potassium activated adenosine triphosphatase of axonal membranes. Tetrodotoxin binding and acetylcholinesterase activities are unaffected by cardiotoxin treatment. The details of association of cardiotoxin with the axonal membrane were studied by following the deactivation of the sodium-potassium activated adenosine triphosphatase and by direct binding measurements with a tritiated derivative of the native cardiotoxin. The maximal binding capacity of the membrane is 42-50 nmol of cardiotoxin/mg of membrane protein. The high amount of binding suggests association of the toxin with the lipid phase of the membrane. It has been shown that cardiotoxin first associates rapidly and reversibly to membrane lipids, then, in a second step, it induces a rearrangement of the membrane structure which produces and irreversible deactivation of the sodium-potassium activated adenosine triphosphatase. Solubilization of the membrane-bound ATPase with Lubrol WX gives an active enzyme species that is resistant to cardiotoxin-induced deactivation. Cardiotoxin binding to the membrane is prevented by high concentrations of Ca 2+ and dibucaine. Although cardiotoxins and neurotoxins of cobra venom have large sequence homologies, their mode of action on membranes is very different. The cardiotoxin seems to bind to the lipid phase of the axonal membrane and inhibits the sodium-potassium activated adenosine triphosphatase, whereas the neurotoxin associates with a protein receptor in the post-synaptic membrane and blocks acetylcholine transmission.

4-Nitrophenylphosphatase↗
PubMed1976

Sea anemone toxin:a tool to study molecular mechanisms of nerve conduction and excitation-secretion coupling.

The effects of polypeptide neurotoxin from Anemonia sulcata on nerve conduction in crayfish giant axons and on frog myelinated fibers have been analyzed. The main features of toxin action are the following: (i) the toxin acts at very low doses and its action is apparently irreversible. (ii) The toxin selectively affects the closing (inactivation) of the Na+ channel by slowing it down considerably; it does not alter the opening mechanism of the Na+ channel or the steady-state potassium conductance. (iii) The tetrodotoxin-receptor association is unaffected by previous treatment of the axonal membrane with the sea anemone toxin. (iv) Conversely, the sea anemone toxin can only associate with the membrane when the Na+ channel is open for Na+; it does not bind when the channel is previously blocked by tetrodotoxin. (v) Besides its effect on the action potential, the sea anemone toxin displays a veratridine-type depolarizing action at low Ca2+ concentration which can be suppressed by tetrodotoxin. The sea anemone toxin greatly stimulates the release of gamma-[3H]aminobutyric acid from neurotransmitter-loaded rat brain synaptosomes. The apparent dissociation constant of the neurotoxin-receptor complex in this system is 20 nM. The sea anemone toxin effect is antagonized by tetrodotoxin.

Action Potentials↗
PubMed1975

Structure-function relationships and site of action of apamin, a neurotoxic polypeptide of bee venom with an action on the central nervous system.

Specific chemical modifications of apamin have been used to study the residues involved in its toxic action. Transformation of Lys4 into homoarginine did not affect toxicity. Modification of the alpha-amino group of Cys1 and of the epsilon-amino group of Lys4 by acetic anhydride or fluorescamine decreased toxicity only by a factor of 2.5-2.8. Modification of the gamma-carboxylate of Glu7 with glycine ethyl ester in the presence of a soluble carbodiimide decreased toxicity by a factor of 2. Diethyl pyrocarbonate treated of the imidazole side chain of His18 decreased toxicity by a factor of 2.6. Thus none of these residues is essential for toxicity. However, combined modification of amino groups and of the imidazole side chain of His-18 completely abolished biological activity. Complete loss of toxicity also resulted from reduction and alkylation of both disulfide bridges, from chemical modification with cyclohexanedione of Arg-13 and Arg-14, and from removal of Arg-14 of acetylated apamin by digestion with trypsin. Incorporation of radioactive acetyl groups on both amino groups of apamin gave an active labeled toxin which has been used to localize the site of action of apamin in the spinal cord, principally in the lumbar part of the neuraxis.

Acetates↗
PubMed1975

Structure-function relationship in the binding of snake neurotoxins to the torpedo membrane receptor.

The Cys30-Cus34 bridge present in all long neutotoxins (71-74 amino acids, 5 disulfide bridges), but not in short toxins (60-63 amino acids, 4 disulfide bridges), is exposed at the surface since it can be reduced rapidly and selectively by sodium borohydride. Reduction and alkylation of the Cys30-Cys34 bridge of Naja haje neurotoxin III hardly alter the conformational properties of this model long toxin. Although alkylation by iodoacetic acid of th -SH groups liberated by reduction abolishes the toxicity, alkylation by iodoacetamide or ethylenimine does not affect the curarizing efficacy of the toxin. The Cys30-Cys34 bridge is not very important for the toxic activity of long neurotoxins. Reduction of the Cys30-Cys34 bridge followed by alkylation with radioactive iodoacetamide gave a labeled and active toxin which is a convenient derivative for binding experiments to the toxin receptor in membranes of the Torpedo electric organ. The binding capacity of these membrane is 1200 pmol of toxin/mg of membrane protein. The dissociation constant of the modified toxin-receptor complex at pH 7.4, 20 degrees is 10 minus 8m. Reduction with carbroxamidomethylation of the Cys30-Cys34 bridge decreases the affinity of the native Naja haje toxin only by a factor of 15. Carboxymethylation after reduction prevents binding to the membrane receptor. The binding properties of the derivative obtained by reduction and aminoethylation of Cys30-Cys34 are very similar to those of native neurotoxin III; the affinity is decreased only by a factor of 5. Binding properties to Toredo membrane of long neurotoxins (Naja haje neurotoxin III) and short neurotoxins (Naje haje toxin I and Naja mossambica toxin I) have been compared. Dissociation constants of receptor-long neurotoxin and receptor-short neurotoxin complexes are very similar (5.7 minus 8.2 times 10(-10) M at pH 7.4, 20degrees. However, the kinetics of complex formation and complex dissociation are quite different. Short neurotoxins associate 6-7 times faster with the toxin receptor and dissociate about 5-9 times faster that long neurotoxins. Acetylation and dansylation of Lys53 and Lys 27 decrease the affinity of long and short toxins for their receptor by a factor of about 200 at pH 7.4, 20 degrees, mainly because of the slower rate of association with the receptor.

Amino Acid Sequence↗