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

Abstract We have characterized the defining members of a novel subfamily of excitatory conotoxins, the short κ A-conotoxins ( κ A S -conotoxins). κ A-conotoxins PIVE and PIVF ( κ A-PIVE and κ A-PIVF) were purified from Conus purpurascens venom. Both peptides elicited excitatory activity upon injection into fish. κ A-PIVE was synthesized for further characterization. The excitatory effects of κ A-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, κ A-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 α A-conotoxins (muscle nAChR antagonists) and κ A-conotoxins (excitotoxins), which all share a common arrangement of cysteine residues (CC–C–C–C–C). Biochemically, the κ A S -conotoxins more closely resemble the α A S -conotoxins than the other κA-conotoxin subfamily, the long κ A-conotoxins ( κ A L -conotoxins); however, κ A S - and α A S -conotoxins produce different physiological effects. In contrast, the κ A S -and κ A L -conotoxins that diverge in several biochemical characteristics are clearly more similar in their physiological effects.