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 voltag e-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 s pecific member of the Kv3 potassium channel family. These toxins, bloo d 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 r eversible manner by BDS-I, with an IC50 value of 47 nM. This inhibitio n is specific because BDS-I failed to block other K+ channels in the K v1, Kv2, Kv3, and Kv4 subfamilies. Inward rectifier K+ channels are al so 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 nM, respec tively. We observed that BDS-I and BDS-II have some sequence homologie s with other sea anemone Na+ channels toxins, such as AsI, AsII, and A xI. However, they had a weak effect on tetrodotoxin-sensitive Na+ chan nels in neuroblastoma cells and no effect on Na+ channels in cardiac a nd skeletal muscle cells. BDS-I and BDS-II are the first specific bloc kers identified so far for the rapidly inactivating Kv3.4 channel.