Phylogenetic specificity of cholinergic ligands: .alpha.-conotoxin SI

Abstract

The .alpha.-conotoxins are small peptide neurotoxins from the venom of fish-hunting cone snails which block nicotinic acetylcholine receptors (nAChRs). We describe the purification, characterization, and chemical synthesis of a new .alpha.-conotoxin from Conus striatus, .alpha.-conotoxin SI. In contrast to other AChR ligands, .alpha.-SI discriminates between different vertebrate nAChRs. The sequence of .alpha.-conotoxin SI is Ile-Cys-Cys-Asn-Pro5-Ala-Cys-Gly-Pro-Lys10-Tyr-Ser-Cys-NH2. This sequence was confirmed by chemical synthesis. A des-Ile-.alpha.-SI derivative was also synthesized and is biologically active. Although .alpha.-conotoxin SI is highly homologous to previously described .alpha.-conotoxins, it has one noteworthy sequence feature which may account for its novel biological specificity. In all other .alpha.-conotoxins, there is a positively charged amino acid at residue 9; in .alpha.-conotoxin SI, this is replaced by proline. The discovery that different .alpha.-conotoxins can vary by orders of magnitude in their apparent affinity for different vertebrate receptors demonstrates that .alpha.-conotoxins will be useful probes for investigating phylogenetic differences between vertebrate nAChRs.