Sea Anemone Peptides with a Specific Blocking Activity against the Fast Inactivating Potassium Channel Kv3.4

Sea anemone venom is known to contain toxins that are active on voltage-sensitive Na + channels, as well as on delayed rectifier K + channels belonging to the Kv1 family. This report describes the properties of a new set of peptides from Anemonia sulcata that act as blockers of a specific member of the Kv3 potassium channel family. These toxins, blood depressing substance (BDS)-I and BDS-II, are 43 amino acids long and differ at only two positions. They share no sequence homologies with other K + channel toxins from sea anemones, such as AsKS, AsKC, ShK, or BgK. In COS-transfected cells, the Kv3.4 current was inhibited in a reversible manner by BDS-I, with an IC 50 value of 47 n m . This inhibition is specific because BDS-I failed to block other K + channels in the Kv1, Kv2, Kv3, and Kv4 subfamilies. Inward rectifier K + channels are also insensitive to BDS-I. BDS-I and BDS-II share the same binding site on brain synaptic membranes, with K 0.5 values of 12 and 19 n m , respectively. We observed that BDS-I and BDS-II have some sequence homologies with other sea anemone Na + channels toxins, such as AsI, AsII, and AxI. However, they had a weak effect on tetrodotoxin-sensitive Na + channels in neuroblastoma cells and no effect on Na + channels in cardiac and skeletal muscle cells. BDS-I and BDS-II are the first specific blockers identified so far for the rapidly inactivating Kv3.4 channel.