A novel polypeptide, designated omega-Lsp-IA, which modulates P-type Ca(2+) channels, was purified from the venom of the spider Geolycosa sp. omega-Lsp-IA contains 47 amino acid residues and 4 intramolecular disulfide bridges. It belongs to a group of spider toxins affecting Ca(2+) channels and presumably forms the inhibitor cystine knot (ICK) fold. Peculiar structural features (a cluster of positively charged residues in the C-terminal loop of the peptide and a regular distribution of hydrophobic residues) that may play a decisive role in the omega-Lsp-IA mechanism of action were located. Recombinant omega-Lsp-IA was produced in prokaryotic expression system and was shown to be structurally and functionally identical to the native toxin. At saturating concentration (10nM), the peptide clearly slows down the activation kinetics and partially inhibits the amplitude of P-current in rat cerebellar Purkinje neurons. Prominent deceleration of the activation kinetics is manifested as the appearance of a five-fold slower component of the current activation. The specificity of action of omega-Lsp-IA on different Ca(2+) channel types was studied in isolated hippocampal neurons of rat. omega-Agatoxin IVA completely removed the effect of omega-Lsp-IA on the whole-cell Ca(2+) current. Therefore, omega-Lsp-IA appears to act specifically on P-type Ca(2+) channels.
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