Alterations of voltage-activated sodium current by a novel conotoxin from the venom of conus gloriamaris

1. The novel peptide toxin δ-conotoxin-GmVIA, recently purified by us from the mollusk-hunting snail Conus gloriamaris, induces convulsive-like contractions when injected into land snails but has no detectable effects in mammals. 2. At concentrations of 0.5 -0.75 μM, the toxin induces action potential broadening and increased excitability of cultured Aplysia neurons. 3. Whole cell patch-clamp experiments on cultured Aplysia neurons revealed that the toxin does not alter potassium or calcium currents, but induces action potential broadening by slowing the inactivation kinetics of the sodium current. Under control conditions, the inactivation kinetics of the sodium current follows a single exponential with τ = 0.47 ± 0.14 (SE) ms. After toxin application the sodium current inactivation is composed of two phases: an early phase with τ = 0.86 ± 0.12 ms and a late phase of slowly inactivating sodium current with τ = 488 ± 120 ms. In addition, the toxin shifts the voltage-dependent steady-state inactivation curve to more positive values and the steady-state activation curve to more negative values. These alterations are not associated with changes in the rise time or the peak value of the sodium. 4. The novel δ-conotoxin-GmVIA, and the previously described 'King Kong peptide,' purified from another mollusk-hunting cone (Conus textile), share a similar cystein framework also found in the calcium channel blocking peptide ω-conotoxin but represent a new class of conotoxins with unusual specificity for molluscan sodium channels.