A NEW CONOTOXIN AFFECTING SODIUM CURRENT INACTIVATION INTERACTS WITH THE DELTA-CONOTOXIN RECEPTOR-SITE

We describe a new peptide conotoxin affecting sodium current inactivat ion, that competes on binding with S-conotoxin TxVIA (delta TxVIA). Th e amino acid sequence of the new toxin, designated conotoxin NgVIA (Ng VIA), is SKCFSOGTFCGIKOGLCCSVRCFSLFCISFE (where O is trans-4-hydroxypr oline). The primary structure of NgVIA has an identical cysteine frame work and similar hydrophobicity as delta TxVIA but differs in its net charge. NgVIA competes with delta TxVIA on binding to rat brain synapt osomes and molluscan central nervous system and strongly inhibits sodi um current inactivation in snail neurons, as does delta TxVIA. In cont rast to delta TxVIA, NgVIA is a potent paralytic toxin in vertebrate s ystems, its binding appears to be voltage-dependent, and it synergical ly increases veratridine-induced sodium influx to rat brain synaptosom es. delta TxVIA acts as a partial antagonist to NgVIA in rat brain in vivo. NgVIA appears to act via a receptor site distinct from that of d elta TxVIA but similar to that of Conus striatus toxin. This new toxin provides a lead for structure function relationship studies in the de lta-conotoxins and will enable analysis of the functional significance of this complex of receptor sites in gating mechanisms of sodium chan nels.