Discovery and characterization of the short kappa A-conotoxins: A novel subfamily of excitatory conotoxins

We have characterized the defining members of a novel subfamily of excitatory conotoxins, the short kappa A-conotoxins (kappa A(S)-conotoxins). kappa A-conotoxins PIVE and PIVF (kappa A-PIVE and kappa A-PIVF) were purified from Conus purpurascens venom. Both peptides elicited excitatory activity upon injection into fish. kappa A-PIVE was synthesized for further characterization. The excitatory effects Of KA-PIVE in vivo were dose dependent, causing hyperactivity at low doses and rapid immobilization at high doses, symptomatic of a type of excitotoxic shock. Consistent with these observations, KA-PIVE caused repetitive action potentials in frog motor axons in vitro. Similar results have been reported for other structurally distinct conotoxin families; such peptides appear to be required by most fish-hunting cone snails for the rapid immobilization of prey. Unexpected structure-function relationships were revealed between these peptides and two families of homologous conotoxins: the alpha A-conotoxins (muscle nAChR antagonists) and kappa A-conotoxins (excitotoxins), which all share a common arrangement of cysteine residues (CC C-C-C-Q. Biochemically, the kappa As-conotoxins more closely resemble the alpha As-conotoxins than the other kappa A-conotoxin subfamily, the long kappa A-conotoxins (kappa A(L)-conotoxins); however, kappa A(S)- and alpha A(S)-conotoxins produce different physiological effects. In contrast, the kappa A(S)-and kappa A(L)-conotoxins that diverge in several biochemical characteristics are clearly more similar in their physiological effects. (c) 2006 Elsevier Ltd. All rights reserved.