The charybdotoxin family of K+ channel-blocking peptides

For many years, neuronal K’ channels were pharmacological orphans, essential membrane proteins against which’ no natural toxins were known. While biochemically and physiologically useful high affinity ligands had been identified for Na’, Ca2+, and many ligand-gated channels, the best blocker available for K+ channels was tetraethylammonium. In 1982, this situation changed with the discovery by Possani and colleagues (Carbone et al., 1982; Possani et al., 1982) of a peptide in the venom of the scorpion Centruroides noxiusthat inhibited K+ currents in theclassical electrophysiological preparation, the squid giant axon. In the ensuing years, a large collection of homologous peptides from scorpions was identified, and these were all found to block either of two major classes of K+ channels, voltage-gated (Kv-type) and high conductance Ca’+activated (BK-type) K’ channels. These toxins inhibit in the 1 pM to 10 nM concentration range, and they act only on K+ channels. My purpose here is to summarize the molecular characteristics of these toxins and to indicate the unique kinds of molecular information they have provided about the K+ channels that act as their receptors. I will not discuss any of the other classes of peptide toxins against K’ channels now recognized, such as apamin (Hughes et al., 1982) leiurotoxin (Chicchi et al., 1988), or dendrotoxin (Parcej and Dolly, 1989; Hurst et al., 1991). First, a word-boring but necessary-on the nomenclature of these peptides, which have been named either whimsically or according to the scorpion species in which the peptide is found. This is an unsatisfactory situation in view of the expanding list of toxin homologs. Whimsical names provided an amusing mnemonic device when only a handful of such toxins had been identified, but our limited imaginations cannot sustain this practice for long; speciesbased names present a double difficulty, since each venom is packed with multiple isoforms, and since very similar toxins are found in widely different species. Accordingly, I suggest a formal name for this family of scorpion venom peptides: the “a-K-toxins,” abbreviated “a-KTxmn,” using a subfamily nomenclature that mirrors modern usage for the K+ channels themselves. Thus, according to the molecular subfamilies shown in Table 1, charybdotoxin will be called a-KTxl .l, noxiustoxin a-KTx2.1, agitoxin 2 a-KTx3.2, etc.