8.B.6 The Ca²⁺Channel-targeting Spider Toxin (CST) Family

A novel polypeptide, designated omega-Lsp-IA, which modulates P-type Ca²⁺ channels, has been purified from the venom of the spider Geolycosa sp. omega-Lsp-IA contains 47 amino acid residues and 4 intramolecular disulfide bridges (Pluzhnikov et al., 2007). It belongs to a group of spider toxins affecting Ca²⁺ channels and may form the inhibitor cystine knot (ICK) fold. A cluster of positively charged residues in the C-terminal loop of the peptide and a regular distribution of hydrophobic residues may play a role in its mechanism of action. 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. Omega-Lsp-IA shows differing effects on different Ca²⁺ channel types. Omega-Agatoxin IVA completely removed the effect of omega-Lsp-IA on the whole-cell Ca²⁺ current. Omega-Lsp-IA appears to act specifically on P-type Ca²⁺channels (Pluzhnikov et al., 2007). 

δ-atracotoxin isoforms (δ-ACTX; 8.B.6.3.1) bind to voltage-gated sodium channels in the same way as classical scorpion alpha-toxins. According to the 'voltage-sensor trapping model', delta-ACTX isoforms interact with the voltage sensor S4 transmembrane segment of alpha-subunit domain IV, thereby preventing its normal outward movement and concurrent conformational changes required for inactivation of the channel. As a consequence, prolonged action potentials at autonomic or somatic synapses induce massive transmitter release, resulting in clinical correlates of neuroexcitation (e.g., muscle fasciculation, spasms, paresthesia, tachycardia and diaphoresis) (Luch 2010).