An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.

/pdf/a-novel-potent-vasoconstrictor-peptide-produced-by-vascular-4zvh0kyupn.pdf

A novel potent vasoconstrictor peptide produced by vascular endothelial cells.

Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.

Na+-channel specific scorpion toxins are peptides of 60-76 amino acid residues in length, tightly bound by four disulfide bridges. The complete amino acid sequence of 85 distinct peptides are presently known. For some toxins, the three-dimensional structure has been solved by X-ray diffraction and NMR spectroscopy. A constant structural motif has been found in all of them, consisting of one or two short segments of alpha-helix plus a triple-stranded beta-sheet, connected by variable regions forming loops (turns). Physiological experiments have shown that these toxins are modifiers of the gating mechanism of the Na+-channel function, affecting either the inactivation (alpha-toxins) or the activation (beta-toxins) kinetics of the channels. Many functional variations of these peptides have been demonstrated, which include not only the classical alpha- and beta-types, but also the species specificity of their action. There are peptides that bind or affect the function of Na+-channels from different species (mammals, insects or crustaceans) or are toxic to more than one group of animals. Based on functional and structural features of the known toxins, a classification containing 10 different groups of toxins is proposed in this review. Attempts have been made to correlate the presence of certain amino acid residues or 'active sites' of these peptides with Na+-channel functions. Segments containing positively charged residues in special locations, such as the five-residue turn, the turn between the second and the third beta-strands, the C-terminal residues and a segment of the N-terminal region from residues 2-11, seems to be implicated in the activity of these toxins. However, the uncertainty, and the limited success obtained in the search for the site through which these peptides bind to the channels, are mainly due to the lack of an easy method for expression of cloned genes to produce a well-folded, active peptide. Many scorpion toxin coding genes have been obtained from cDNA libraries and from polymerase chain reactions using fragments of scorpion DNAs, as templates. The presence of an intron at the DNA level, situated in the middle of the signal peptide, has been demonstrated.

Scorpion toxins specific for Na+-channels.

https://www.hal.inserm.fr/inserm-00378020/document

Voltage-gated ion channels and gating modifier toxins

A recently described peptide hormone, endothelin, is a potent vasoconstrictor, but it is unclear whether endothelin has other biological actions These experiments extend the range of biological actions of endothelin to stimulation of mitogenesis Endothelin at low concentrations (01-10 nM) induced mitogenesis by quiescent rat glomerular mesangial cells in culture Mitogenesis induced by endothelin was accompanied by activation of phospholipase C with increased inositol phosphate turnover and increments of intracellular [Ca2+] Endothelin also activated Na+/H+ exchange, causing cytosolic alkalinization, and enhanced transcription of the c-fos protooncogene, additional biochemical signals closely linked to proliferation In addition to being a vasoconstrictor, endothelin thus also functions as a mitogen, presumably through activation of phospholipase C

/pdf/endothelin-stimulates-phospholipase-c-na-h-exchange-c-fos-52jw84b95k.pdf

Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression, and mitogenesis in rat mesangial cells.

The complete covalent structure of the insect toxin purified from the venom of the North-African scorpion Androctonus australis Hector was described. Its amino acid sequence was established by phenylisothiocyanate degradation of several protein derivatives and proteolytic fragments in a liquid protein sequencer using either a "protein" or a "peptide" program. The position of the four disulfide bridges were deduced by analysis of proteolytic peptides before and after diperformic oxidation, and by partial labeling of the half cystine residues with [14C]-iodoacetic acid and determining the specific radioactivities of the S-[14C]-carboxymethylated phenylthiohydantoin cysteines. The sequences of the insect and mammal toxins from scorpions can be aligned with homology with the positions of seven half-cystine residues as registers. The mammal and insect toxins have three disulfide bridges at homologous positions. The mammal and insect toxins have three disulfide bridges at homologous positions. The fourth bridge is different in that Cys12 in mammal toxin II is replaced by Cys38 in the insect toxin. It is likely that the position of the disulfide bridges is the same for all scorpion neurotoxins active on mammals. We believe that the shift of one half-cystine residue in the insect toxin may induce a conformational change in the structure of the protein, which, in turn, may partially account for the total specificity of this toxin for insect nervous system.

Covalent structure of the insect toxin of the North African scorpion Androctonus australis Hector.

Two neurotoxins (BmK I and BmK II) from the venom of the scorpion Buthus martensi Karsch: purification, amino acid sequences and assessment of specific activity

Purification and Chemical and Biological Characterizations of Seven Toxins from the Mexican Scorpion, Centruroides suffusus suffusus"

The positions of the disulfide bridges in toxin II of Androctonus australis Hector were investigated using proteolytic enzymes. The resulting peptides were separated by column and paper chromatography and high-voltage electrophoresis. Determination of the amino acid compositions of the cystine-containing peptides or their oxidized derivatives and, when necessary, dansyl Edman degradation allowed to locate the disulfide bonds in the toxin. The four disulfide bridges were found to link the half-cystine residues number 12 and 63, 16 and 36, 22 and 46, 26 and 48. These positions are probably the same in all scorpion neurotoxins.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1974.tb03716.x

Disulfide bonds of toxin II of the scorpion Androctonus australis Hector.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2890%2980607-K

Charles Kopeyan

Papers

Covalent structure of the insect toxin of the North African scorpion Androctonus australis Hector.

Two neurotoxins (BmK I and BmK II) from the venom of the scorpion Buthus martensi Karsch: purification, amino acid sequences and assessment of specific activity

Purification and Chemical and Biological Characterizations of Seven Toxins from the Mexican Scorpion, Centruroides suffusus suffusus"

Disulfide bonds of toxin II of the scorpion Androctonus australis Hector.

Primary structure of scorpion anti-insect toxins isolated from the venom of Leiurus quinquestriatus quinquestriatus.