A new family of conotoxins that blocks voltage-gated sodium channels

Conus peptides, including ω-conotoxins and α-conotoxins (targeting calcium channels and nicotinic acetylcholine receptors, respectively) have been useful ligands in neuroscience. In this report, we describe a new family of sodium channel ligands, the μO-conotoxins. The two peptides characterized, μO-conotoxins MrVIA and MrVIB from Conus marmoreus potently block the sodium conductance in Aplysia neurons. This is in marked contrast to standard sodium channel blockers that are relatively ineffective in this system. The sequences of the peptides are as follows. μO-conotoxin MrVIA: ACRKKWEYCIVPIIGFIYCCPGLICGPFVCV μO-conotoxin MrVIB: ACSKKWEYCIVPILGFVYCCPGLICGPFVCV μO-conotoxin MrVIA was chemically synthesized and proved indistinguishable from the natural product. Surprisingly, the μO-conotoxins show no sequence similarity to the μ- conotoxins. However, an analysis of cDNA clones encoding the μO-conotoxin MrVIB demonstrated striking sequence similarity to ω- and δ-conotoxin precursors. Together, the ω, δ, and μO-conotoxins define the O-superfamily of Conus peptides. The probable biological role and evolutionary affinities of these peptides are discussed.