New conopeptides of the D-superfamily selectively inhibiting neuronal nicotinic acetylcholine receptors

The venom of cone snails (Conus spp.) is a rich source of peptides exhibiting a wide variety of biological activities. Several of these conopeptides are neuronal nicotinic acetylcholine receptor (nAChR) antagonists and belong to the A-, M-, S-, C and the recently described D-superfamily (alpha D-conopeptides). Here we describe the discovery and characterization of two alpha D-conopeptides isolated from the venom of Conus mustelinus and Conus capitaneus. Their primary structure was determined by Edman degradation, MS/MS analysis and by a PCR based approach. These peptides show close structural homology to the alpha D-VxXIIA, -B and -C conopeptides from the venom of Conus vexillum and are dimers (about 11 kDa) of similar or identical peptides with 49 amino acid residues and a characteristic arrangement of ten conserved cysteine residues. These novel types of conopeptides specifically block neuronal nAChRs of the alpha 7, alpha 3 beta 2 and alpha 4 beta 2 subtypes in nanomolar concentrations. Due to their high affinity, these new ligands may provide a tool to decipher the localisation and function of the various neuronal nAChRs. (C) 2009 Elsevier Ltd. All rights reserved.