This program will develop the Conus system as a general source of novel peptide ligands. The pace with which molecular genetics continues to define new molecular forms of cell surface receptors and ion channels is constantly accelerating; the need to characterize the functional biology of each of these newly-defined receptor subtypes increases correspondingly. Thus, agents which can disrupt the function of specific receptor subtypes are urgently required; this program aims to provide such subtype-discriminating ligands using peptides from Conus. The program supports three scientific cores: (a) a Conus venom resource core, which includes a molecular biology component, (b) a peptide sequencing and synthesis core and (c) an electrophysiology core. Together these cores support a core peptide discovery program to develop new conus peptide ligands. The program consists of three major projects, each divided into three subprojects. The goal of the projects is to study three important classes of receptor targets for which a well-developed set of Conus peptide probes are already available. The focus of each project is: Project I - omega-conotoxins and Ca++ channels; Project II - Cholinergic Conus peptides and nicotinic acetylcholine receptors and Project III - Conantokins and NMDA receptors.