A NEW FAMILY OF CONOTOXINS THAT BLOCKS VOLTAGE-GATED SODIUM-CHANNELS

Conus peptides, including omega-conotoxins and alpha-conotoxins (targe ting calcium channels and nicotinic acetylcholine receptors, respectiv ely) have been useful ligands in neuroscience. In this report, we desc ribe a new family of sodium channel ligands, the mu O-conotoxins. The two peptides characterized, mu O-conotoxins MrVIA and MrVIB from Conus marmoreus potently block the sodium conductance in Aplysia neurons. T his is in marked contrast to standard sodium channel blockers that are relatively ineffective in this system. The sequences of the peptides are as follows. mu O-conotoxin MrVIA: ACRKKWEYCIVPIIGFIYCCPGLICGPFVCV mu O-conotoxin MrVIB: ACSKKWEYCIVPILGFVYCCPGLICGPFVCV mu O-conotoxin M rVIA was chemically synthesized and proved indistinguishable from the natural product. Surprisingly, the mu O-conotoxins show no sequence si milarity to the mu-conotoxins. However, ananalysis of cDNA clones enco ding the mu O-conotoxin MrVIB demonstrated striking sequence similarit y to omega- and delta-conotoxin pre cursors. Together, the omega-, del ta-, and mu O-conotoxins define the O-superfamily of Conus peptides. T he probable bio logical role and evolutionary affinities of these pept ides are discussed.