A new conotoxin affecting sodium current inactivation interacts with the δ-conotoxin receptor site

We describe a new peptide conotoxin affecting sodium current inactivation, that competes on binding with δ-conotoxin TxVIA (δTxVIA). The amino acid sequence of the new toxin, designated conotoxin NgVIA (NgVIA), is SKCFSOGTFCGIKOGLCCSVRCFSLFCISFE (where O is trans-4-hydroxyproline). The primary structure of NgVIA has an identical cysteine framework and similar hydrophobicity as δTxVIA but differs in its net charge. NgVIA competes with δTxVIA on binding to rat brain synaptosomes and molluscan central nervous system and strongly inhibits sodium current inactivation in snail neurons, as does δTxVIA. In contrast to δTxVIA, NgVIA is a potent paralytic toxin in vertebrate systems, its binding appears to be voltage-dependent, and it synergically increases veratridine-induced sodium influx to rat brain synaptosomes. δTxVIA acts as a partial antagonist to NgVIA in rat brain in vivo. NgVIA appears to act via a receptor site distinct from that of δTxVIA but similar to that of Conus striatus toxin. This new toxin provides a lead for structure-function relationship studies in the δ-conotoxins and will enable analysis of the functional significance of this complex of receptor sites in gating mechanisms of sodium channels.