Characterization of two Bunodosoma granulifera toxins active on cardiac sodium channels

Two sodium channel toxins, Bg II and Bg III, have been isolated and purified from the sea anemone Bunodosoma granulifera . Combining different techniques, we have investigated the electrophysiological properties of these toxins. We examined the effect of Bg II and Bg III on rat ventricular strips. These toxins prolong action potentials with EC 50 values of 60 and 660 n M and modify the resting potentials. The effect on Na + currents in rat cardiomyocytes was studied using the patch‐clamp technique. Bg II and Bg III slow the rapid inactivation process and increase the current density with EC 50 values of 58 and 78 n M , respectively. On the cloned hH1 cardiac Na + channel expressed in Xenopus laevis oocytes, Bg II and Bg III slow the inactivation process of Na + currents (respective EC 50 values of 0.38 and 7.8 μ M ), shift the steady‐state activation and inactivation parameters to more positive potentials and the reversal potential to more negative potentials. The amino acid sequences of these toxins are almost identical except for an asparagine at position 16 in Bg II which is replaced by an aspartic acid in Bg III. In all experiments, Bg II was more potent than Bg III suggesting that this conservative residue is important for the toxicity of sea anemone toxins. We conclude that Bg II and Bg III, generally known as neurotoxins, are also cardiotoxic and combine the classical effects of sea anemone Na + channels toxins (slowing of inactivation kinetics, shift of steady‐state activation and inactivation parameters) with a striking decrease on the ionic selectivity of Na + channels.British Journal of Pharmacology (2001) 134 , 1195–1206; doi: 10.1038/sj.bjp.0704361