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

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